8-heteroaryl xanthine adenosine A2B receptor antagonists

ABSTRACT

The present invention relates generally to compounds of formula (I): 
                         
wherein
         X is a five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen; and   G 1  and G 2  are independently CH or N.       
     The present invention also relates to the preparation of the compounds, pharmaceutical formulations thereof, and their use in medicine as potent or selective A 2B  adenosine receptor antagonists and their uses for treating asthma, autoimmune diseases and retinal vascular diseases.

RELATED APPLICATION

This application is a division of U.S. application Ser. No. 10/357,865 filed Feb. 3, 2003, now U.S. Pat. No. 7,205,403, which claims the benefit of U.S. Provisional Application No. 60/353,317, filed Feb. 1, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to compounds having antagonistic activity on adenosine A_(2B) receptors. Such compounds are useful in medicaments for treating diseases responsive to reduced levels of A_(2B) receptors as well as use as radioligands for studying biological activity associated with the adenosine A_(2B) receptor.

Adenosine (Ado) is an autocoid (or local hormone) that modulates numerous functions in the cardiovascular and other organ systems. The actions of Ado are mediated by at least four subtypes of cell surface receptors called A₁, A_(2A), A_(2B), and A₃. Because the ubiquity of adenosine receptors (AdoRs) throughout the body of a human, their indiscriminate activation may cause undesirable side effects. Therefore, new drug design approaches to achieve receptor and organ selectivity are needed.

Recently significant advancement has been made in the understanding of the molecular pharmacology and physiology of A_(2B) adenosine receptors. However, due to the lack of highly potent and selective ligands for this receptor subtype, many questions about the patho-physiological role of A_(2B) receptors have not yet been answered (Feoktistov and Biaggioni, 1997; Feoktistov and Biaggioni, 1998). A_(2B) receptors have been implicated in the regulation of mast cell secretion (Feoktistov and Biaggioni 1995), gene expression (Boyle et al. 1996), cell growth (Dubey et al., 1996), intestinal functions (Murthy et al., 1995), neurosecretion (Mateo et al., 1995), vascular tone (Haynes et al., 1995) and asthma (Feoktistov et al., 1998).

U.S. Pat. No. 6,117,878 to Linden discloses the use of 8-phenyl substituted xanthines for the treatment of diseases induced by activation of the adenosine A_(2B) receptor and mast cell activation. These disease states are disclosed as including asthma, myocardial reperfusion injury, allergic reactions including rhinitis, poison ivy induced responses, urticaria, scleroderma arthritis, other autoimmune diseases and inflammatory bowel diseases. In general, antagonists of the A_(2B) adenosine receptor subtype are disclosed to have anti-inflammatory action. U.S. Pat. No. 6,117,878 to Linden is incorporated by reference.

U.S. Patent Application 2002/0002142 to Belardinelli et al. discloses the use of A_(2B) adenosine receptor antagonist compounds for inhibiting mammalian cell proliferation in cells that express the A_(2B) adenosine receptor including human retinal endothelial cells (HREC). Belardinelli discloses such treatment for ischemic injury to retinal vessels, for example, microvascular abnormalities of the retina, retinopathy, prematurity, macular degeneration, and diabetic retinopathy. U.S. Patent Application 2002/0002142 to Belardinelli et al. is incorporated by reference.

The use of A_(2B) antagonists as antiasthmatic agents is supported by the experimental observation that theophylline and enprofylline are used as therapeutic agents (Feoktistov and Biaggioni 1997; Feoktistov et al., 1998). Theophylline is an alkyl-xanthine that is a weak nonselective adenosine antagonist (See Linden et al., Cardiovascular Biology of Purines, eds. G. Burnstock, et al., 1998, pp. 1-20.) However, its use is associated with unpleasant side effects, such as insomnia and diuresis. (See Vassallo et al., Mayo. Clin. Proc. 1998, 73, 346-354). In recent years, the use of theophylline as a bronchodilator, for relief of asthma, has been supplanted by drugs of other classes, i.e., selective β₂-adrenergic agonists, corticosteroids, and recently leukotriene antagonists. (See Drazen et al., New Eng. J. Med. 1999, 340, 197-206.). These compounds also have limitations, thus, the development of a theophylline-like drug with reduced side effects is still desirable.

It has been recognized that theophylline and its closely related analogue caffeine block endogenous adenosine acting as a local modulator of adenosine receptors in the brain and other organs at therapeutically useful doses. (See Fredholm et al., Pharmacol. Rev. 1999, 51, 83-133.). In comparison to the other known actions of theophylline, e.g., inhibition of phosphodiesterases, theophylline is more potent in antagonism of adenosine receptors.

As noted the xanthine derivative, enprofylline, is also used to treat asthma. Enprofylline has been reported to block A_(2B) adenosine receptors. However, this compounds only weakly blocks A₁, A_(2A) and A₃ adenosine receptors.

It has been reported that therapeutic concentrations of theophylline or enprofylline block human A_(2B) receptors, and it has been proposed that antagonists selective for this subtype may have potential use as antiasthmatic agents. (See Feoktistov et al., Pharmacol. Rev. 1997, 49, 381-402; and Robeva et al., Drug Dev. Res. 1996, 39, 243-252. Enprofylline has a reported K_(i) value of 7 μM and is somewhat selective in binding to human A_(2B) adenosine receptors. (See Robeva et al., Drug Dev. Res. 1996, 39, 243-252 and Linden et al., Vol. Pharmacol. 1999, 56, 705-713.)

Adenosine A_(2B) receptors are expressed in some mast cells, such as the BR line of canine mastocytoma cells, which appear to be responsible for triggering acute Ca²⁺ mobilization and degranulation. (See Auchampach et al., Mol. Pharmacol. 1997, 52, 846-S60 and Forsyth et al., Inflamm. Res. 1999, 48, 301-307.) Adenosine A_(2B) receptors also trigger Ca²⁺ mobilization, and participate in a delayed IL8 release from human HMC-1 mast cells. Other functions associated with the A_(2B) AR are the control of cell growth and gene expression, (See Neary et al., Trends Neurosci. 1996, 19, 13-18.) endothelial-dependent vasodilation (See Martin et al., J Pharmacol. Exp. Ther. 1993, 265, 248-2,53.), and fluid secretion from intestinal epithelia. (See Strohmeier, et al., J Biol. Chem. 1995, 270, 2387-2394.) Adenosine acting through A_(2B) receptor subtype has also been reported to stimulate chloride permeability in cells expressing the cystic fibrosis transport regulator. (See Clancy et al., Am. J Physiol. 1999, 276, C361-C369.)

Both of these xanthine derivatives, enprofylline and theophylline, are proven to be effective but with low potency and selectivity at the A_(2B) adenosine receptor subtype (theophylline A_(2B) binding affinity K_(i)=13 μM; enprofylline A_(2B) binding affinity K_(i)=7 μM).

Asthma is a complex disease involving the concerted actions of multiple inflammatory and immune cells, spasmogens, inflammatory mediators, cytokines and growth factors. Theophylline has significant side effects that may be related to its A₁ receptor antagonism. It is therefore believed that more potent and selective A_(2B) receptor antagonists will provide enhanced asthma treatment.

The A₁, A_(2A) and A₃ adenosine receptors have been pharmacologically characterized through the use of highly potent and selective agonists and/or antagonists. In contrast the study of A_(2B) receptor has been precluded due to the lack of selective ligands. Researchers such as Jacobson and his coworkers have proposed using the radioligand of 7-amino-2-(2-4-furyl)-5-[2-(4-hydroxy-phenyl)ethyl]-amino[1,2,4]-triazolo-[1,5-a][1,3,5]-triazine ([³H]-ZM241385) as useful radioligand for studying the A_(2B) adenosine receptor subtype (Ji et al., 1999) even though [³H]-ZM241385 has a K_(D) value of 34 nM.

Jacobson and coworkers have also reported some xanthine derivatives endowed with good affinity to the adenosine receptors but without significant selectivity for the human A_(2B) adenosine receptor subtype (Kim et al., 1999; Jacobson et al., 1999). Some non-xanthine derivatives closely related to ZM 241385 have also been synthesized, but, while some of the reported compounds displayed significant affinity to A_(2B) receptors, none of them possessed relevant selectivity versus the other receptor subtypes A₁, A_(2A) and A₃ (De Zwart et al., 1999).

Similarly, Jacobson and coworkers, with the aim of obtaining non-xanthine antagonists for A_(2B) receptors, modified the structure of 5-amino-9-chloro-2-(2-furanyl)[1,2,4]triazolo-[1,5-c]-quinazoline (CGS 15943), a non selective adenosine receptor antagonist, which appeared to be a suitable starting compound for adenosine receptor antagonists by appropriate substitutions at different positions. In particular an improvement of affinity to A_(2B) receptors was observed when aminoacidic chains are appended to the amino group of position 5 (Kim et al., 1998).

U.S. Pat. No. 5,935,964 to Baraldi et al. discloses triazolo pyrimidines have antagonist affinity for the A_(2A) receptor. Using these compounds as a starting point, Baraldi et al. investigated a series of pyrazolo[4,3-e]1,2,4-triazolo-[1,5-c]pyrimidine compounds for use as A_(2B) receptor antagonists. In particular the compounds with the free amino group at the 5-position, and for example, a phenylethyl chain at the N8 pyrazole nitrogen show good affinity to A_(2B) adenosine receptors. However, none of these compounds demonstrated good selectivity (Baraldi et al., 2001).

Linden, Jacobson and coworkers have also reported a series of anilide derivatives of 8-phenyl-xanthine carboxylic congeners that proved to be potent and selective A_(2B) antagonists (Kim et al., 2000; Ji et al., 2001) and S-substituted 1,3,7-trialkyl xanthine derivatives (U.S. Pat. No. 5,861,405 to Jacobson et al.) While many of the Linden and Jacobson compounds have high adenosine A_(2B) potency, selectivity against other human adenosine receptors are in most cases limited (PCT patent application WO 00/73307 by Linden, Jacobson et al., 2000).

We have now discovered additional novel xanthine compounds having high antagonist affinity for the A_(2B) receptor with varying levels of affinity and superior selectivity compared to compounds previously reported. The above noted references are incorporated herein by reference.

BRIEF SUMMARY OF THE INVENTION

Compounds useful as potent, yet selective modulators of adenosine receptors, with activity as adenosine A_(2B) receptor antagonists, and, in some cases A₁ or A₃ antagonists, and methods of preparation and use thereof, are disclosed.

The compounds of the present invention have the following general formula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons;

X is an optionally substituted five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen;

M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ to C₈)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or —S(O)₂—;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ may independently form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —OCH═CH—, —CH═CH—CH═CH, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ to C₅)alkynyl;

or a pharmaceutically acceptable salt thereof.

In another aspect this invention provides compounds of formula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C8)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons;

X is a five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen, optionally substituted by one or two substituents selected from the group consisting of lower alkyl, amino, hydroxy, alkyloxy, acyloxy and acylamino;

M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ to C₈)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, —S(O)₂—; or a carbon substituted with a lower alkyl;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ to C₅)alkynyl;

or a pharmaceutically acceptable salt thereof.

In a further aspect, this invention provides compounds of the following formula (II):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄aralkenyl, or (C₈ to C₁₄)aralkynyl;

R³ is H or (C₁ to C₈)alkyl;

R⁹ is independently a phenyl or pyrazole ring; a phenyl or pyrazole ring substituted at any position with amino, lower alkyl, or carboxyl; or a phenyl or pyrazole ring substituted at any two positions with a substituent selected from amino, lower alkyl, and carboxyl; or

R⁹ is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the invention provides compounds of formula (III):

wherein

-   -   R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to         C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to         C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R⁸ is phenyl, substituted phenyl, (C, to C₈)alkyl, or benzyl;

or a pharmaceutically acceptable salt thereof

The compounds can be used in a method for the treatment of diseases mediated by adenosine A_(2B) receptors. Such diseases include, but are not limited to chronic and acute inflammatory diseases involving degranulation of mast cells including asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, allergic rhinitis, allergic dermatitis and bee sting; impaired sensitivity to insulin including Type 2 diabetes or non-insulin dependent diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis including solid tumors and angiogenic retinopathies; and apnea of preterm infants; myocardial reperfusion injury, inflammatory bowel disease, and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), and lupus erythematosis.

Similarly, the compounds can be used in a method for the treatment of diseases involving microvascular abnormalities of the retina that are mediated by adenosine A_(2B) receptors. Such diseases include, but are not limited to, retinopathy, prematurity, macular degeneration, and diabetic retinopathy.

The compounds can be used in a pharmaceutical formulation that includes a compound of the present invention and one or more excipients. Various chemical intermediates can be used to prepare the compounds of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1illustrates competition binding curves for compound AS29 to human cloned A₁, A_(2a), A_(2b), and A₃ adenosine receptors;

FIG. 2 illustrates competition binding curves for compound AS57 to human cloned A₁, A_(2a), A_(2b), and A₃adenosine receptors;

FIG. 3 illustrates competition binding curves for compound AS64 to human cloned A₁, A_(2a), A_(2b), and A₃ adenosine receptors;

FIG. 4 illustrates competition binding curves for compound AS68 to human cloned A₁, A_(2a), A_(2b), and A₃ adenosine receptors; and

FIG. 5 illustrates a Comparison between binding and functional data.

DETAILED DESCRIPTION OF THE INVENTION

The present application discloses compounds useful as potent, yet selective antagonists of adenosine receptors with particular utility with the adenosine A_(2B) receptor subtype, methods of preparation and use thereof.

The compounds can be used in a pharmaceutical formulation that includes a compound of the present invention and one or more excipients. Various chemical intermediates can be used to prepare the compounds of the present invention.

The compounds of the present invention have the following general formula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons;

X is an optionally substituted five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen;

M is a (C₁ to C₈)alkylene, (C₂ to C8)alkenylene, or (C₂ to C₈)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or —S(O)₂—;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ may independently form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ to C₅)alkynyl;

or a pharmaceutically acceptable salt thereof.

In another aspect this invention provides compounds of formula (I):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl;

A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons;

X is a five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen, optionally substituted by one or two substituents selected from the group consisting of lower alkyl, amino, hydroxy, alkyloxy, acyloxy and acylamino;

M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ to C₈)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, —S(O)₂—; or a carbon substituted with a lower alkyl;

G¹ and G² are independently CH or N;

R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulfhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or

taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—;

R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅) alkenyl, or (C₂ to C₅)alkynyl;

or a pharmaceutically acceptable salt thereof.

In a further aspect, this invention provides compounds of the following formula (II):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R³ is H or (C₁ to C₈)alkyl;

R⁹ is independently a phenyl or pyrazole ring; a phenyl or pyrazole ring substituted at any position with amino, lower alkyl, or carboxyl; or a phenyl or pyrazole ring substituted at any two positions with a substituent selected from amino, lower alkyl, and carboxyl; or

R⁹ is selected from the group consisting of

or a pharmaceutically acceptable salts thereof.

In yet another aspect, the invention provides compounds of formula (III):

wherein

R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl;

R⁸ is phenyl, substituted phenyl, (C₁ to C₈)alkyl, or benzyl;

or a pharmaceutically acceptable salt thereof

As used herein the term “very potent adenosine A_(2B) receptor antagonist” means a compound able to prevent the inhibition of an adenosine A_(2B) receptor agonist and having a binding to human adenosine A_(2B) receptor (K_(i)) of less than 2000 nM, preferably less than 150 nM, and most preferably less than 50 nM. The term “highly potent adenosine A_(2B) receptor antagonist” means a very potent adenosine A_(2B) receptor antagonist having a binding affinity to human adenosine A_(2B) receptor (K_(i)) of less than 150 nM.

As used herein the term “highly selective adenosine A_(2B) receptor antagonist” means a very potent adenosine A_(2B) receptor antagonist having a binding affinity to human adenosine receptor subtypes A₁, A_(2A) and A₃ (K_(i)) of greater than 1,000 nM.

As used herein the term “lower alkyl” means a monovalent radical, straight or branched chain, derived from the corresponding alkane having one to ten carbon atoms, i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl (all isomers), etc. Likewise, “lower alkylene” means a divalent radical of the corresponding alkane. Further, as used herein, other moieties having names derived from alkanes, such as alkoxyl, alkanoyl, alkenyl, cycloalkenyl, etc. when modified by “lower,” have carbon chains of ten or less carbon atoms. In those cases where the minimum number of carbons are greater than one, e.g., alkenyl (minimum of two carbons) and cycloalkyl, (minimum of three carbons), it is to be understood that “lower” means at least the minimum number of carbons.

As used herein the term “amino acid” means an alpha amino acid selected from those amino acids that naturally occur in proteins but without regard for specific stereochemical properties. The term “protected amino acid” means an amino acid of which the alpha amino group has been converted to a less reactive moiety, but a moiety that can be converted back to the amino group with relative ease. The terms “amino acid residue” and “amino acid moiety” are use synonymously herein.

As used herein, the term “substituted alkyl” refers to an alkyl group, preferably of from 1 to 10 carbon atoms (“substituted lower alkyl”), having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, hydroxyamino, alkoxyamino, nitro, —S(O)-alkyl, —S(O)-substituted alkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-substituted alkyl, —S(O)₂-aryl, —S(O)₂-heteroaryl, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic. As used herein, other moieties having, the prefix “substituted” are intended to include one or more of the substituents listed above.

As used herein, the term “alkoxy” refers to the group “alkyl-O—”, where alkyl is as defined above. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

As used herein, the term “alkenyl” refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂), and the like.

As used herein, the term “alkynyl” refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.

As used herein, the term “acyl” refers to the groups alkyl-C(O)—, substituted alkyl C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

As used herein, the term “acylamino” refers to the group —C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or heterocyclic, wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

As used herein, the term “aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring, (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from I to 5 substituents and preferably 1 to 3 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —S(O)-alkyl, —S(O)-substituted alkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-substituted alkyl, —S(O)₂-aryl, —S(O)₂-heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.

As used herein, the term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 12 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like.

As used herein, the terms “halo” or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro, bromo or chloro.

As used herein, the term “heteroaryl” refers to an aromatic carbocyclic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).

Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with from 1 to 5 substituents and preferably 1 to 3 substituents selected from the group consisting of acyloxy, hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —S(O)-alkyl, —S(O)-substituted alkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-substituted alkyl, —S(O)₂-aryl, —S(O)₂-heteroaryl, trihalomethyl. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).

“Heterocycle” or “heterocyclic” refers to a monovalent saturated or unsaturated carbocyclic group having a single ring or multiple condensed rings, from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring. Such heterocyclic groups are optionally substituted with 1 to 5 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy, thioaryloxy, trihalomethyl, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings.

As to any of the above groups that contain 1 or more substituents, it is understood, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.

“Pharmaceutically acceptable salts” refers to pharmaceutically acceptable salts of a compound of the general formula of the present invention, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like can be used as the pharmaceutically acceptable salt.

The term “protecting group” or “blocking group” refers to any group which when bound to one or more hydroxyl, amino or carboxyl groups of the compounds (including intermediates thereof such as the aminolactams, aminolactones, etc.) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, amino or carboxyl group. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), and the like which can be removed by conventional conditions compatible with the nature of the product.

Those skilled in the art of organic chemistry will appreciate that reactive and fragile functional groups often must be protected prior to a particular reaction, or sequence of reactions, and then restored to their original forms after the last reaction is completed. Usually groups are protected by converting them to a relatively stable derivative. For example, a hydroxyl group may be converted to an ether group and an amino converted to an amide or carbamate. Methods of protecting and de-protect, also know as “blocking” and “de-blocking,” are well know and widely practiced in the art, e.g., see T. Green, Protective Groups in Organic Synthesis, John Wiley, New York (1981) or Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie, Plenum Press, London (1973).

Representative example compounds include:

Compound Number Compound Name AS3 8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H- purine-2,6-dione AS4 [3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetra-hydro-1H-purin-8-yl)isoxazol-5- yl]methyl-benzoate AS7 8-(1-methyl-4-nitro-1H-pyrrol-2-yl)-1,3-dipropyl-3,7-dihydro-1H-purine- 2,6-dione AS8 4-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-pur-in-8-yl)-1- methyl-1H-pyrazol-3-yl]amino}-4-oxobutanoic acid AS9 tert-butyl 4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8- yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutylcarbamate AS10 4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]amino}-4-oxobutan-1-aminium chloride AS11 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-phenylacetamide AS12 2-(2,4-dichlorophenoxy)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro- 1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS13 2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro- 1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS14 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-isobutylphenyl)acetamide AS15 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide AS16 2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro- 1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS17 2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro- 1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS18 (2S)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]-2-phenylpropanamide AS19 (2R)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]-2-phenylpropanamide AS20 {3-[(E)-2-(1,3-dipropyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin- 8-yl)vinyl]isoxazol-5-yl}methyl benzoate AS21 2-(4-chlorophenoxy)-N-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS22 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide AS23 2-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro- 1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS24 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide AS25 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide AS26 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide AS27 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-chlorophenyl)acetamide AS28 2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9- tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS29 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)acetamide AS30 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]- oxy}phenyl)acetamide AS31 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide AS32 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide AS33 ethyl 4-[(E)-2-(7-methyl-1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)vinyl]-1-methyl-1H-pyrrole-2-carboxylate AS35 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-5-yl]-2-phenylacetamide AS36 8-(1-methyl-3-nitro-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H- purine-2,6-dione AS37 8-(5-amino-1-methyl-1H-pyrazol-3-yl)-1,3-dipropyl-3,7--dihydro-1H- purine-2,6-dione AS38 8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H- purine-2,6-dione AS40 N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]-2-phenylacetamide AS43 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide AS44 2-(2,3,4-trimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9- tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS53 N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7- tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea AS54 N-(3-chlorophenyl)-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H- purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea AS55 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea AS56 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl- 2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS57 2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9- tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide AS58 N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yl]-2-(4-hydroxy-3-methoxyphenyl)acetamide AS59 N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide AS60 N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H- purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide AS61 N-(4-fluorophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H- purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide AS62 2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-5-yl]oxy}-N-(4-fluorophenyl)acetamide AS63 2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methy-1-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide AS64 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide AS65 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide AS66 2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methy-1-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide AS67 2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methy-1-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide AS68 N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro- 1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide AS69 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide AS1 1,3-di-n-propyl-8-(1-methyl-5-carboxy-1-H-pyrazol-3-yl)-xanthine AS49 1-[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1- methyl-1H-pyrazol-3-yl]-3-(4-methoxy-phenyl)-urea AS91 1,3-di-n-propyl-8-{5-[(4-sec-butyl-phenylcarbamoyl)-methoxy]-2- methyl-2H-pyrazole-3-yl}-xanthine AS92 1,3-di-n-propyl-8-{5-[(4-methyl-phenylcarbamoyl-methoxy]-2-methyl- 2H-pyrazole-3-yl}-xanthine AS93 1,3-di-n-propyl-8-{5-[(4-(morpholine-4-yl)-phenylcarbamoyl)-methoxy]- 2-methyl-2H-pyrazole-3-yl}-xanthine AS95 1,3-di-n-propyl-8-{5-[(4-carboxy-phenylcarbamoyl)-methoxy]-2-methyl- 2H-py-razole-3-yl}-xanthine AS99 1,3-di-n-propyl-8-{5-[(3,4-dime-thyl-phenylcarbamoyl)-methoxy]-2- methyl-2H-pyrazole-3-yl}-xanthine AS100 1,3-di-n-propyl-8-{5-[(3,4-dimethyl-phenylcar-bamoyl)-methoxy]-2- methyl-2H-pyrazole-3-yl}-xanthine AS101 1,3-di-n-propyl-8-{5-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-2- methyl-2H-pyrazole-3-yl}-xanthine AS89 1,3-di-n-propyl-8-{5-[(pyri-din-4yl)-methoxy]-2-methyl-2H-pyrazole-3- yl}-xanthine AS70 1,3-di-n-propyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2- methyl-2H-pyrazole-3-yl}-xanthine AS72 8-(5-{2-[4-(4-Fluoro-pheny-1)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl- 2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione AS87 1,3-di-n-propyl-8-{5-[2-Oxo-2-(4-methyl-piperazin-1-yl)-ethoxy]-2- methyl-2H-pyrazole-3-yl}-xanthine AS90 8-(5-{2-[4-(4-Benzyl-pheny-1)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl- 2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione AS96 1,3-di-allyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl- 2H-pyrazole-3-yl}-xanthine AS74 1,3-di-n-propyl-8-{3-[(3,4-me-thylendioxy-phenylcarbamoyl)-methoxy]- isoxazol-5-yl}-xanthine AS76 1,3-di-n-propyl-8-{3-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-isoxazol- 5-yl}-xanthine AS73 1,3-di-n-propyl-8-{3-[(4-fluoro--phenylcarbamoyl)-methoxy]-isoxazol-5- yl}-xanthine AS75 1,3-di-n-propyl-8-{3-[(4-methoxy-phenylcarbamoyl)-methoxy]-isoxazol- 5-yl}-xanthine AS81 1,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-metho-xy]-pyridin-3- yl}-xanthine AS85 1,3-di-n-propyl-8-{6-[(4-iodo-pheny-lcarbamoyl)-methoxy]-pyridazin-3- yl}-xanthine AS68a N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-diallyl-2,3,6,9-tetrahydro- 1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide AS94 1,3-di-n-propyl-8-{5-[(4-(ethoxycarbonyl)-phenylcarbamoyl)-methoxy]- 2-met-hyl-2H-pyrazole-3-yl}-xanthine AS103 1,3-di-n-propyl-8-(2-hydroxypyridin-5-yl)-xanthine AS105 1,3-diallyl-8-{5-[2-oxo-2-(4-(pyridin-2-yl)-piperazin-1-yl)-ethoxy]-2- met-hyl-2H-pyrazole-3-yl}-xanthine AS106 1,3-diallyl-8-{5-[2-oxo-2-(4-(pyrimidin-2-yl)-piperazin-1-yl)-ethoxy]-2- m-ethyl-2H-pyrazole-3-yl}-xanthine AS109 1,3-di-n-propyl-8-{5-[(4-(aminosulfonyl)phenylcarbamoyl)-methoxy]-2- methy-1-2H-pyrazole-3-yl}-xanthine Synthesis of Compounds

The compounds of the present invention may be synthesized by any suitable means. However, the 8-heteroaryl-xanthine derivatives of the present invention are preferably synthesized by condensation of a suitably substituted heteroaryl-carboxylic acid with a 1,3-disubstituted-5,6-diaminouracil to form an amide, which is subsequently cyclized to give a 1,3-disubstituted-8-heteroaryl-xanthine.

If desired, reaction of this product under conditions commonly employed by one skilled in the art would provide additional compounds of the present invention. For example, 1,3-disubstituted-8-heteroaryl-xanthines containing a primary amine on the heteroaryl moiety could be further reacted with an appropriate carboxylic acid, acid halide, carboxylic acid ester, or isocyanate under conditions widely known to those skilled in the art to provide the corresponding amides or ureas of the present invention.

Similarly, the 1,3-disubstituted-8-heteroaryl-xanthines containing a hydroxyl group attached to the heteroaryl moiety might be reacted with a suitable acyl ester, acid halide, α-halocarbonyl compound, isocyanate, sulfinyl halide or sulfonyl halide to afford the respective ester, β-oxycarbonyl compound, carbamate, sulfinate, or sulfonate. A further example can be seen in which a 1,3-disubstituted-8-heteroaryl-xanthine containing a carboxylic acid attached to the heteroaryl moiety may be reacted with an appropriate aniline, heteroarylamine, alkylamine, or aralkylamine to afford the corresponding amide.

It will be recognized by one skilled in the art that numerous other possibilities are conceivable in the substituent attached to the heteroaryl moiety and the functional group it is reacted with. It will also be recognized that the suggested additional reactions are not exhaustive, but merely illustrative.

In general, the compounds of the present invention are prepared as depicted in the accompanying schemes. As shown in Scheme 1, a 1,3-disubstituted-5,6-diaminouracil (Compound 2) may be dissolved in an appropriate volume of a lower alcohol with an appropriate heteroaryl carboxylic acid (Compound 3) and a suitable coupling agent, such as 3-ethyl-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) or 1,3-dicyclohexylcarbodiimide (DCC), at a temperature of 5 to 70° C., for a period of 1 to 24 hours.

After removing the residual solvent, the intermediate amide is treated with an excess of an aqueous basic solution, such as sodium hydroxide or potassium hydroxide at a temperature of 30 to 100° C. for 1 to 12 hours to afford the desired 8-(aminoheteroaryl)-1,3-disubstituted-xanthine (Compound 4).

After cooling the resulting clear aqueous solution to room temperature, the solution is typically acidified to approximately pH=5 using a suitable inorganic acid, such as concentrated HCl, until the intermediate 8-(aminoheteroaryl)-1,3-disubstituted-xanthine precipitates. The precipitated intermediate may then be collected by filtration or centrifugation further purifying, if desired, by recrystallization from an appropriate solvent or combination of solvents or by chromatography.

A solution of the requisite carboxylic acid (Compound 5) may then be converted to the corresponding acyl halide by suspending in the appropriate halogenating reagent, such as thionyl chloride, phosphorus oxychloride, thionyl bromide, phosphorus trichloride, or phosphorus tribromide, optionally in the presence of a suitable solvent, such as methylene chloride, chlorform, 1,2-dichloroethane, 1,4-dioxane, or diethyl ether, and warming to between 30 and 90° C. for 1 to 18 hours.

After removal of the excess halogenating reagent, a solution of the intermediate 8-(aminoheteroaryl)-1,3-disubstituted-xanthine and a suitable base, such as triethylamine, diethylisopropylamine, or diisopropylethylamine, is added to the acyl halide dissolved in an appropriate solvent. After stirring the mixture at 10 to 80° C. for 1 to 36 hours, the mixture is evaporated, and the residue partitioned between an organic solvent and a saturated aqueous solution of sodium bicarbonate. After drying the organic extract, the desired product is typically purified by column chromatography on silica gel.

Alternatively, compounds of the present invention may be prepared as depicted in Scheme 2. In this sequence, 1,3-disubstituted-5,6-diaminouracils (Compound 2) may be condensed with heteroarylcarboxylic acids possessing an ethoxycarbonylmethoxy group attached to the heteroaryl moiety. Such condensation may be effected by treating a solution of the 1,3-disubstituted-5,6-diaminouracil (Compound 2) in an appropriate volume of a lower alcohol with the desired heteroaryl carboxylic acid (Compound 6) and a suitable coupling agent, such as 3-ethyl-1-(3-dimethylaminopropy-1)-3-ethylcarbodiimide hydrochloride (EDCl) or 1,3-dicyclohexylcarbodiimid-e (DCC), at a temperature of 5 to 70° C., for a period of 1 to 24 hours.

After removing the residual solvent, the intermediate amide is treated with an excess of an aqueous basic solution, such as sodium hydroxide or potassium hydroxide at a temperature of 30 to 100° C. for 15 minutes to 12 hours to afford the desired 8-(carboxymethoxy-heteroaryl)-1,3-disubstituted-xanthine (Compound 7).

Condensation of the intermediate xanthine (Compound 7) with a suitable aniline, or heteroaromatic amine (Compound 8) affords the desired products following normal purification procedures. This condensation is typically performed in dimethylformamide, or other suitable solvent, such as dimethylacetamide, hexamethylphosphortriamide, or ethyl acetate, using EDCl and HOBt to promote the amide bond formation at temperatures of 10 to 90° C. for periods of 10 minutes to 24 hours.

It will be recognized that a variety of other condensation procedures, all well known in the art, such as the use of DCC or the conversion of the carboxylic acid to an activated ester and displacement with the amine, will also result in the preparation of the desired compounds.

In another illustrative synthesis example, Scheme 3, the intermediate Compound 4, dissolved in an appropriate solvent such as anhydrous 1,4-dioxane, methylene chloride, 1,2-dichloroethane, or 1,2-dimethoxyethane, is treated with a suitable isocyanate (Compound 9) at room temperature or above for a period of 4 to 24 hours to afford the desired 8-heteroaryl)xanthine ureas. The desired products are typically precipitated by the addition of water, followed by column chromatography purification on silica gel.

5,6-Diamino-1,3-dimethyluracil, 5,6-diamino-1,3-diallyluracil, and 5,6-diamino-1,3-diropylluracil are commercially available. The 5,6-diamino-1,3-diisobutyluracil may be prepared as previously described (M. Merlos, et al., Eur. J. Med. Chem. 25: 652 (1990).). The synthesis of 1-methyl-3-benzyloxy-carbonylamino-pyrazole-5-carboxylic acid and 1-methyl-5-benzyloxycarbonylamino-pyrazole-3-carboxylic acid follows the method of Lee and Cain (J. Org. Chem. 54: 428 (1989)).

The synthesis of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetate and ethyl (5-carboxy-1-methylpyrazoi-3-yl)oxyacetate has been described by Sucrow and coworkers (Chem. Ber. 109: 253 (1976) and Chem. Ber. 109: 268 (1976)). 1-Methyl-4-nitroimidazole-2-carboxylate is prepared as described by Krowicki and Lown (J. Org. Chem. 52: 3493 (1987)). 1-Methyl-4-nitropyrrole-2-carboxylate is commercially available. Aicher and coworkers (J. Med. Chem. 41: 4556 (1998)) recently described the preparation of 3-substituted-5-hydroxymethyl-isoxazoles, which are readily acylated using methods well known to those skilled in the art.

The 4-(substituted)-benzyloxyphenylacetic acids not commercially available may be prepared from methyl 4-hydroxyphenylacetate and the appropriate benzyl halides, as described by Muller, Reindl, and Breu (J. Med. Chem. 44: 814 (2001)) for 4-(3-methoxybenzyloxy)phenylacetic acid. All other starting materials are generally available from normal commercial sources.

The following examples are provided in a non-limiting manner to further illustrate the methods of synthesis and use of the compounds of the present invention.

EXAMPLE 1 Preparation Of Compound AS3

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol), 1-methyl-3-(benzyloxycarbonylamino)-pyrazole-5-carboxylic acid (0.8 g, 0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred at room temperature for two hours. Excess CH₃OH was evaporated in vacuo to give a yellow solid that was collected by filtration and washed with H₂O to give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmed to 70-80° C. for three hours. The clear aqueous solution was cooled and acidified to pH 5 with concentrated HCl. The white precipitate that formed was collected by filtration and washed with H₂O to afford the desired 1,3-dipropyl-8-(3-amino-i-methylpyrazol-5-yl)xanthine, which was recrystallized from CH₃OH.

MP: 285-288° C.; .¹H-NMR (DMSO-d₆): δ0.93 (m, 6H), 1.58 (m, 2H), 1.75 (m, 2H), 3.88 (bs, 2H), 4.01 (s, 5H), 6.21 (s, 1H), 13.51 (bs, 1H).

EXAMPLE 2 Preparation of Compound AS11

A solution of phenylacetic acid (0.196 mmol) in 3 mL of thionyl chloride was stirred at 70° C. for four hours, then excess thionyl chloride removed in a nitrogen stream. A solution of 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (0.151 mmol, Example 1) and 0.04 mL of anhydrous triethylamine in 10 mL of CH₂Cl₂: CH₃OH (1:1) was added and the mixture was stirred at room temperature for 24 hours, monitoring by TLC.

At completion, the solvent was evaporated, the residue dissolved in ethyl acetate, and the solution washed with saturated aqueous NaHCO₃ and brine. The organic layer was dried (Na₂SO₄), filtered, and evaporated in vacuo. The desired product was purified by column chromatography on silica gel.

MP: 139-140° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (q, 6H, J=5.18 Hz), 1.59 (q, 2H), J=7.18 Hz), 1.72 (q, 2H, J=7.06 Hz), 3.62 (s, 2H), 3.88 (t, 2H, J=6.72 Hz), 3.98 (t, 2H), J=6.96 Hz), 4.12 (s, 3H), 7.25-7.33 (m, 6H), 10.8 (s, 1H), 14.02 (s, 1H).

EXAMPLE 3 Preparation of Compound AS12

Using 2,4-dichlorophenoxyacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 225-226° C.; .¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72 (m, 2H), 3.85 (t, 2H), 4.01 (t, 2H), 4.14 (s, 3H), 4.87 (s, 2H), 7.10 (d, 1H), 7.33 (m, 2H), 7.60 (d, 1H), 10.80 (s, 1H), 14.02 (s, 1H).

EXAMPLE 4 Preparation of Compound AS13

Using 3-methoxyphenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 158-159° C.; .¹H-NMR (DMSO-d₆): δ 0.89 (q, 6H, J=7.13 Hz), 1.62 (q, 2H), 1.72 (q, 2H), 3.59 (s, 2H), 3.74 (s, 3H), 3.85 (t, 2H), 4.00 (t, 2H), 4.13 (s, 3H), 6.92 (s, 1H), 7.30 (m, 4H), 10.77 (s, 1H), 14.00 (s, 1H).

EXAMPLE 5 Preparation of Compound AS14

Using 4-(2-methylpropyl)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 124-126° C.; .¹H-NMR (DMSO-d₆): δ 0.85 (m, 12H, J=6.52 Hz), 1.39 (d, 2H, J=6.87 Hz), 1.75 (m, 5H), 2.41 (d, 2H, J=7.1 Hz), 3.85 (t, 2H, J=6.94 Hz), 4.00 (t, 2H), 4.10 (s, 3H), 7.11 (d, 1H), 7.30 (m, 4H, J=8.05 Hz), 10.70 (s, 1H), 13.99 (s, 1H).

EXAMPLE 6 Preparation of Compound AS15

Using 4-nitrophenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 285-287° C.; .¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H, J=6.83 Hz), 1.55 (q, 2H, J=6.83 Hz), 1.72 (q, 2H, J=7.05 Hz), 3.89 (d, 4H), 4.00 (t, 2H), 4.13 (s, 3H), 7.27 (s, 1H), 7:63 (d, 2H, J=8.47 Hz), 8.18 (d, 2H, J=8.34 Hz), 10.87 (s, 1H), 13.90 (s, 1H).

EXAMPLE 7 Preparation of Compound AS16

Using 4-(benzyloxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 184-185° C.; .¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.59 (q, 2H, J=6.98 Hz), 1.69 (q, 2H, J=7.1 Hz), 3.54 (s, 2H), 3.85 (t, 2H), 3.98 (t, 2H), 4.13 (s, 3H), 5.00 (s, 2H), 6.98 (d, 1H), 7.28 (m, 9H, J=6.46 Hz), 10.75 (s,1H), 14.02 (s, 1H).

EXAMPLE 8 Preparation of Compound AS17

Using 4-hydroxyphenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS 3).

MP: 145-150° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.55 (m, 2H), 1.72 (m, 2H), 3.40 (s, 2H), 3.85 (t, 2H), 3.98 (t, 2H), 4.10 (s, 311), 6.69 (d, 2H, J=8), 7.31 (s, 1H), 9.20 (s,1H), 10.70 (s, 1H), 14.0 (s, 1H1).

EXAMPLE 9 Preparation of Compound AS18

Using (S)-2-phenylpropanoic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 125-126° C.; .¹H-NMR (CDCl₃): δ 0.85 (m, 6H), 1.57 (s,3H), 1.59 (m, 2H), 1.61 (m, 2H), 1.70 (m, 1H), 4.1 (m, 4H), 4.16 (s, 3H), 7.37 (m, 5H), 7.39 (s, 1H), 7.90, (s, 1H), 12.8(s, 1H).

EXAMPLE 10 Preparation of Compound AS19

Using (R)-2-phenylpropanoic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 125-126° C.; 1H-NMR (CDCl₃): δ 0.85 (m, 6H), 1.57 (s, 3H), 1.59 (m, 2H), 1.61 (m, 2H), 1.70 (m, 1H), 4.1 (m, 4H), 4.16 (s, 3H), 7.37 (m, 5H), 7.39 (s, 1H), 7.90 (s, 1H), 12.8 (s, 1H).

EXAMPLE 11 Preparation of Compound AS21

Using 4-chlorophenoxyacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 260-261° C.; .¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72 (m, 2H), 3.85 (t, 2H), 3.98 (t, 2H), 4.14 (s, 3H), 6.98 (d, 2H, J=8.0 Hz), 7.36 (d, 2H, J=8.0 Hz), 7.33 (s, 1H), 10.80 (s, 1H), 14.02 (s, 1H).

EXAMPLE 12 Preparation of Compound AS22

Using 4-fluorophenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 176° C.; .¹H-NMR (DMSO-d₆). δ 0.88 (m, 6H), 1.60 (m, 2H), 1.70 (m, 2H), 3.60 (s, 2H), 3.70 (s, 3H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.15 (m, 2H), 7.31 (m, 2H), 7.30 (s, 1H), 10.70 (s, 1H), 14.0 (s, 1H).

EXAMPLE 13 Preparation of Compound AS23

Using 4-methoxyphenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 125-126° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 3.50 (s, 2H), 3.70 (s, 3H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.15 (m, 2H), 7.31 (m, 2H), 7.30 (s, 1H), 10.70 (s, 1H), 14.0 (s, 1H).

EXAMPLE 14 Preparation of Compound AS24

Using 3-chlorophenylacetic acid and 1,3-dipropyl-8-(3-amino-i1-methypyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 143-145° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 611), 1.50 (m, 2H), 1.70 (m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.30 (m, 4H), (s, 1H), 10.8 (s, 1H), 14.0 (s, 1H).

EXAMPLE 15 Preparation of Compound AS25

Using 3-fluorophenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 148-150° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.10 (m, 4H), 7.30 (s, 1H), 10.8 (s, 1H), 14.0 (s, 1H).

EXAMPLE 16 Preparation of Compound AS26

Using 4-(dimethylamino)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 215° C.; .¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 2.80 (s, 6H), 3.60 (s, 2H), 3.80 (t, 2H)?, 4.00 (t, 2H), 4.10 (s, 3H), 6.67 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 7.29 (s, 1H), 10.8 (s, 1H), 14.0 (s, 1H).

EXAMPLE 17 Preparation of Compound AS27

Using 4-chiorophenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 159-161° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.29 (s, 1H), 7.32 (d, 2H, J=8.0 Hz), 7.38 (d, 2H, J=8.0 Hz), 10.8 (s, 1H), 14.0 (s, 1H).

EXAMPLE 18 Preparation of Compound AS28

Using 3,4-(dimethoxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 140-142° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.55 (q, 2H), 1.72 (q, 2H), 3.50 (s, 2H), 3.74 (s, 6H), 3.82 (t, 2H), 4.02 (t, 2H), 4.13 (s, 3H), 6.88 (m, 3H, J=3.58), 6.96 (d, 1H), 7.33 (s, 1H), 10.73 (s, 1H).

EXAMPLE 19 Preparation of Compound AS29

Using 4-(2-trifluoromethylbenzyloxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 184-186° C.; .¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.59 (q, 2H), 1.69 (q, 2H), 3.54 (s, 2H), 3.85 (t, 2H), 4.00 (t, 2H), 4.12 (s, 3H), 5.20 (s, 2H), 6.92 (d, 1H), 7.28 (m, 3H, J=5.48), 7.73 (m, 4H, J=6.55), 10.75 (s, 1H), 14.02 (s, 1H).

EXAMPLE 20 Preparation of Compound AS30

Using 4-(3-trifluoromethylbenzyloxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 218-220° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H, J=5.06), 1.55 (q, 2H, J=6.88), 1.72 (q, 2H, J=7.47), 3.55 (s, 2H), 4.01 (t, 2H), 4.08 (t, 2H), 4.12 (s, 3H), 5.20 (s, 2H), 5.76 (s, 1H), 7.00 (d, 1H), 7.68 (t, 3H), 7.80 (m, 4H), 10.75 (s, 1H), 14.01 (s, 1H).

EXAMPLE 21 Preparation of Compound AS31

Using 4-(4-nitrobenzyloxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 136-139° C.; .¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (q, 2H), 1.72 (q, 2H), 3.55 (s, 2H), 4.01 (t, 2H), 4.08 (t, 2H), 4.12 (s, 3H), 5.20 (s, 2H), 7.00 (d, 1H), 7.48 (t, 4H), 7.80 (d, 2H), 8.30 (d, 2H), 10.75 (s, 1H).

EXAMPLE 22 Preparation of Compound AS32

Using 4-(trifluoromethyl)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 240° C.; .¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (q, 2H), 1.72 (q, 2H), 3.75 (s, 2H), 3.89 (t, 2H), 4.01 (t, 2H), 4.08 (s, 3H), 7.27 (s, 1H), 7.68 (d, 2H), 7.80 (d, 2H), 10.85 (s, 1H).

EXAMPLE 23 Preparation of Compound AS43

Using 3,4-difluorophenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 250-252° C.;. ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.50 (m, 2H), 1.70 (m, 2H), 3.60 (s, 2H), 3.80 (t, 2H), 4.00 (t, 2H), 4.10 (s, 3H), 7.29 (s, 1H), 7.32 (m, 3H), 10.80 (s, 1H), 14.00 (s, 1H).

EXAMPLE 24 Preparation of Compound AS44

Using 3,4,5-(trimethoxy)phenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 298-300° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (q, 2H), 1.72 (q, 2H), 3.54 (s, 2H), 3.62 (s, 3H), 3.75 (s, 6H), 3.85 (t, 2H), 4.01 (t, 2H), 4.13 (s, 3H), 6.66 (s, 2H), 7.33 (s, 1H), 10.74 (s, 1H), 14.01 (s, 1H).

EXAMPLE 25 Preparation of Compound AS56

Using 4-(benzyloxy)-3-methoxyphenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 205-208° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.55 (m, 2H), 1.72 (m, 2H), 3.54 (s, 2H), 3.76 (s, 3H), 3.85 (t, 2H), 4.01 (t, 2H), 4.13 (s, 3H), 5.04 (s, 2H), 6.84 (d, 1H), 6.98 (d, 2H), 7.38 (m, 6H, J=8.36), 10.72 (s, 1H).

EXAMPLE 26 Preparation of Compound AS57

Using 3,4-methylenedioxyphenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 138-140° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.58 (m, 2H), 1.71 (m, 2H), 3.52 (s, 2H), 3.85 (t, 2H), 4.00 (t, 2H), 4.12 (s, 3H), 5.97 (s, 2H), 6.83 (m, 3H), 7.27 (s, 1H), 10.71 (s, 1H), 14.00 (s, 1H).

EXAMPLE 27 Preparation of Compound AS58

Using 4-hydroxy-3-methoxyphenylacetic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 185° ° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.58 (m, 2H), 1.71 (m, 2H), 3.40 (s, 2H), 3.81 (s, 3H), 3.83 (t, 2H), 3.88 (t, 2H), 4.12 (s, 3H), 6.70 (s, 1H), 6.90 (s, 1H), 7.30 (s, 1H), 8.80 (s, 1H), 10.71 (s, 1H), 14.00 (s, 1H).

EXAMPLE 28 Preparation of Compound AS8

A solution of succinic anhydride and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3) in 1,4-dioxane was heated at 60° C. overnight, the solvent removed, and the residue purified by column chromatography on silica gel to provide the desired product.

MP: 265-266° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.55 (m, 2H), 1.72 (m, 2H), 3.31 (s, 2H), 3.34 (s, 2H), 3.65 (t, 2H), 3.98 (t, 2H), 4.01 (s, 3H), 7.33 (s, 1H), 10.50 (s, 1H), 12.10 (s, 1H), 14.01 (s, 1H).

EXAMPLE 29 Preparation of Compound AS9

Using 4-(t-butyloxycarbonylamino)butanoic acid and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: 215-216° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.37 (s, 9H), 1.66 (m, 6H), 2.28 (m, 2H), 2.91 (m, 2H), 3.86 (t, 2H), 4.01 (t, 2H), 4.12 (s, 3H), 7.30 (s, 1H), 10.50 (s, 1H), 14.01 (s, 1H).

EXAMPLE 30 Preparation of Compound AS10

A solution of 1,3-dipropyl-8-(3-(4-(t-butyloxycarbonylamino)-1-oxo-butylamino)-1-methyl-pyrazol-5-yl)xanthine (Example 29) in 1,4-dioxane was treated with excess ethereal HCl (2 N) at room temperature for 16 hours, during which a white solid precipitated. This was collected by filtration, washing with diethyl ether to afford the desired product as the hydrochloride salt.

MP: 251-252° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.59 (m, 2H), 1.72 (m, 4H), 2.45 (m, 2H), 2.81 (t, 2H), 3.86 (t, 2H), 3.98 (t, 2H), 4.12 (s, 3H), 7.30 (s, 1H), 7.95 (s, 3H), 10.62 (s, 1H), 14.02 (s, 1H).

EXAMPLE 31 Preparation of Compound AS38

A solution of 1,3-dimethyl-5,6-diaminouracil (0.7 g, 0.003 mol), 1-methyl-3-(benzyloxycarbonylamino)-pyrazole-5-carboxylic acid (0.8 g, 0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred at room temperature for two hours. Excess CH₃OH was evaporated in vacuo to give a yellow solid that was collected by filtration and washed with H₂O to give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmed to 70-80° C. for three hours. The clear aqueous solution was cooled and acidified to pH 5 with concentrated HCl. The white precipitate that formed was collected by filtration and washed with H₂O to afford the desired 1,3-dimethyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine, which was recrystallized from CH₃OH.

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 3.20 (s, 3H), 3.40 (s, 3H), 4.00 (s, 3H), 5.50 (s, 2H), 6.20 (s, 1H), 13.20 (s, 1H).

EXAMPLE 32 Preparation of Compound AS40

Using phenylacetic acid and 1,3-dimethyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 31).

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 3.20 (s, 3H), 3.40 (s, 3H), 3.60 (s, 2H), 4.10 (s, 3H), 7.30 (s, 1H), 7.40 (m, 5H), 10.80 (s, 1H), 14.00 (s, 1H).

EXAMPLE 33 Preparation of Compound AS7

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol), 1-methyl-4-nitropyrrole-2-carboxylic acid (0.8 g, 0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred at room temperature for two hours. Excess CH₃OH was evaporated in vacuo to give a yellow solid that was collected by filtration and washed with H₂O to give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmed to 70-80° C. for three hours. The clear aqueous solution was cooled and acidified to pH 5 with concentrated HCl. The white precipitate that formed was collected by filtration and washed with H₂O to afford the desired 1,3-dipropyl-8-(1-methyl-4-nitropyrrol-2-yl)xanthine, which was recrystallized from CH₃OH.

MP: 295-297° C.; ¹H-NMR (DMSO-d₆): δ 0.86 (m, 6H), 1.55 (m, 2H), 1.72 (m, 2H), 3.88 (t, 2H), 3.98 (t, 2H), 3.99 (s, 3H), 7.52 (s, 1H), 8.20 (s, 1H), 14.00 (s, 1H).

EXAMPLE 34 Preparation of Compound AS36

Using 1,3-dipropyl-5,6-diaminouracil and 1-methyl-4-nitroimidazole-2-carboxylic acid.

EXAMPLE 35 Preparation of Compound AS33

Using 1,3-dipropyl-5,6-diaminouracil and 3-(2-ethoxycarbonyl-1-methylpyrrol-4-yl)acrylic acid.

MP: 210-211° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.30 (t, 3H), 1.59 (m, 2H), 1.72 (m, 2H), 3.85 (s, 3 H), 4.03 (s, 3 H), 4.10 (q, 2H), 7.10 (d, 2H), 7.59 (d, 2H), 7.60 (s, 1H).

EXAMPLE 36 Preparation of Compound AS59

To a solution of ethyl (5-carboxy-1-methypyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-vloxy]acetic acid.

Condensation of 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (0.5 mmol) and 5-methyl-2-aminopyridine (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 278-280° C.; ¹H-NMR (DMSO-d₆): δ 0.90 (m, 6H, J=4.66 Hz), 1.55 (m, 2H, J=7.38 Hz), 1.67 (m, 2H, J=7.34 Hz), 2.24 (s, 3H), 3.89 (t, 2H, J=7.34 Hz), 4.00 (t, 2H), J=7.14 Hz), 4.05 (s, 3H), 4.82 (s, 2H), 6.44 (s, 1H), 7.64 (dd, 1H), 7.93 (d, 1H), 8.15 (d, 1H), 10.43 (s, 1H), 13.95 (bs, 1H).

EXAMPLE 37 Preparation of Compound AS64

Using 4-fluoroaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-vloxy]acetic acid (Example 36).

MP: 264° C.; 1H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.55 (q, 2H), 1.59 (q, 2H), 3.86 (t, 2H), 4.00 (t, 2H), 4.07 (s, 3H), 4.76 (s, 2H), 6.50 (s, 1H), 7.16 (m, 2H, J=8.75 Hz), 7.64 (m, 2H, J=5.04), 10.20 (s, 1H).

EXAMPLE 38 Preparation of Compound AS65

Using 4-bromoaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-vloxy]acetic acid (Example 36).

MP: 264° C.; ¹H-NMR (DMSO-d₆): δ 0.90 (m, 6H), 1.59 (m, 2H), 1.71 (m, 2H), 3.86 (t, 2H), 4.00 (t, 2H), 4.06 (s, 3H), 4.77 (s, 2H), 6.50 (s, 1H), 7.52 (m, 4H), 10.26 (s, 1H).

EXAMPLE 39 Preparation of Compound AS68

Using 3,4-methylenedioxyaniline and 2-[5-(13-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36).

MP: 272-273° C.; ¹H-NMR (DMSO-d₆): δ 0.89 (m, 6H), 1.60 (m, 2H), 1.70 (m, 2H), 3.90 (t, 2H), 3.98 (t, 2H), 4.07 (s, 3H), 4.73 (s, 2H), 5.98 (s, 2H), 6.52 (s, 1H), 6.88 (d, 1H, J=8.44 Hz), 7.01 (d, 1H), 7.32 (s, 1H), 10.01 (s, 1H).

EXAMPLE 40 Preparation of Compound AS69

Using 4-acetylaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36).

MP: 273-275° C.; ¹H-NMR (DMSO-d₆): δ 0.90 (m, 61H, J=7.34Hz), 1.74 (m, 4H, J=6.97 Hz), 2.60 (s, 3H), 4.00 (bt, 2H), 4.14 (t, 2H), 4.19 (s, 3H), 4.86 (s, 2H), 6.60 (s, 1H), 7.85 (d, 2H, J=8.58 Hz), 7.96 (d, 2H, J=8.69Hz), 8.82 (s, 1H), 12.95 (bs, 1H).

EXAMPLE 41 Preparation of Compound AS66

To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.

Condensation of 2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (0.5 mmol) and 4-fluoroaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 227-230° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (t, 12H, J=7.58Hz), 2.05 (bm, 2H), 3.74 (d, 2H, J=7.15 Hz), 3.85 (d, 2H, J=7.15), 4.06 (s, 2H), 4.76 (s, 2H), 6.51 (s, 1H), 7.16 (t, 2H), 7.64 (m, 2H), 10.17 (s, 1H), 13.96 (bs, 1H).

EXAMPLE 42 Preparation of Compound AS67

Condensation of 2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 44, Compound AS35, 0.5 mmol) and 4-bromoaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 258-260° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (t, 12H, J=7.22Hz), 2.06 (m, 2H), 3.77 (d, 2H, J=7.3 Hz), 3.85 (d, 2H, J=7.16), 4.06 (s, 3H), 4.77 (s, 2H), 6.51 (s, 1H), 7.52 (dd, 4H, J=8.88 Hz), 10.26 (s, 1H), 13.96 (s, 1H).

EXAMPLE 43 Preparation of Compound AS37

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol), 1-methyl-5-(benzyloxycarbonylamino)-pyrazole-3-carboxylic acid (0.8 g, 0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred at room temperature for two hours. Excess CH₃OH was evaporated in vacuo to give a yellow solid that was collected by filtration and washed with H₂O to give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmed to 70-80° C. for three hours. The clear aqueous solution was cooled and acidified to pH 5 with concentrated HCl. The white precipitate that formed was collected by filtration and washed with H₂O to afford the desired 1,3-dipropyl-8-(5-amino-1-methylpyrazol-3-yl)xanthine, which was recrystallized from CH₃OH.

MP: 249-250° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72 (m, 2H), 3.50 (s, 3H), 3.85 (m, 2H), 3.95 (m, 2H), 5.50 (d, 2H), 6.00 (s,1H), 13.50 (s, 1H).

EXAMPLE 44 Preparation of Compound AS35

A solution of phenylacetic acid (0.196 mmol) in 3 mL of thionyl chloride was stirred at 70° C. for four hours, then excess thionyl chloride removed in a nitrogen stream. A solution of 1,3-dipropyl-8-(5-amino-1-methylpyrazol-3-yl)xanthine (0.151 mmol, Example 43) and 0.04 mL of anhydrous triethylamine in 10 mL of CH₂Cl₂: CH₃OH (1:1) was added and the mixture was stirred at room temperature for 24 hours, monitoring by TLC.

At completion, the solvent was evaporated, the residue dissolved in ethyl acetate, and the solution washed with saturated aqueous NaHCO₃ and brine. The organic layer was dried (Na₂SO₄), filtered, and evaporated in vacuo. The desired product was purified by column chromatography on silica gel.

MP: 279-281° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.55 (m, 2H), 1.72 (m, 2H), 3.60 (s, 3H), 3.75 (s, 2H), 3.89 (t, 2H), 4.01 (t, 2H), 7.27 (s, 1H), 6.90 (s, 1H), 7.20 (m, 5H), 10.20 (s, 1H), 14.00 (s, 1H).

EXAMPLE 45 Preparation of Compound AS60

To a solution of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[3-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid.

Condensation of 2-[3-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid (0.5 mmol) and 4-bromoaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 242° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.70 (m, 4H), 3.70 (s, 3H), 3.85 (t, 2H), 3.98 (t, 2H), 4.85 (s, 2H), 6.32 (s, 1H), 7.62 (dd, 4H, J=8 Hz), 10.33 (s, 1H), 13.70 (s, 1H).

EXAMPLE 46 Preparation of Compound AS61

Condensation of 2-[3-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid (Example 45, 0.5 mmol) and 4-fluoroaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 262° C.; ¹H-NMR (DMSO-d₆): δ 0.88 (m, 6H), 1.70 (m, 4H), 3.70 (s, 3H), 3.85 (t, 2H), 3.98 (t, 2H), 4.85 (s, 2H), 6.32 (s, 1H), 7.18 (t, 2H, J=8.88Hz), 7.62 (m, 2H, J=6.92 Hz), 10.25 (s, 1H), 13.70 (s, 1H).

EXAMPLE 47 Preparation of Compound AS62

To a solution of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[3-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid.

Condensation of 2-[3-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid (0.5 mmol) and 4-fluoroaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 251-252° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (t, 12H), 2.10 (m, 2H), 3.75 (s, 3H), 3.83 (dd, 4H), 4.86 (s, 2H), 6.32 (s, 1H), 7.18 (t, 2H, J=8.85 Hz), 7.62 (m, 2H, J=5.03 Hz), 13.70 (s, 1H).

EXAMPLE 48 Preparation of Compound AS63

Condensation of 2-[3-(1,3-diisobutyl-xanthin-8-yl)-1-methyl-pyrazol-5-yloxy]acetic acid (xanthine intermediate from Example 47, 0.5 mmol) and 4-bromoaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 234° C.; ¹H-NMR (DMSO-d₆): δ 0.84 (t, 12H), 2.10 (m, 2H), 3.73 (s, 3H), 3.831 (dd, 4H), 4.85 (s, 2H), 6.26 (s, 1H), 7.53 (q, 4H), 10.36 (s, 1H), 13.64 (s, 1H).

EXAMPLE 49 Preparation of Compound AS4

A solution of 1,3-dipropyl-5,6-diaminouracil (0.7 g, 0.003 mol), 3-(benzoyloxymethyl)-oxazole-5-carboxylic acid (0.8 g, 0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH was stirred at room temperature for two hours. Excess CH₃OH was evaporated in vacuo to give a solid that was collected by filtration and washed with H₂O to afford the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH was warmed to 70-80° C. for three hours. The clear aqueous solution was cooled and acidified to pH 5 with concentrated HCl. The white precipitate that formed was collected by filtration and washed with H₂O to afford the desired 1,3-dipropyl-8-[3-(benzoyloxymethyl)-oxazol-5-yl]xanthine, which was recrystallized from CH₃OH.

MP: 236-238° C.; ¹H-NMR (DMSO-d₆): δ 0.96 (m, 6H), 1.49 (m, 2H), 1.59 (m, 2H), 3.88 (t, 2H), 3.98 (bs, 2H), 5.60 (s, 2H), 7.25 (s, 1H), 7.74 (m, 3H), 8.00 (m, 2H), 14.50 (s,1 H).

EXAMPLE 50 Preparation of Compound AS20

Using 1,3-dipropyl-5,6-diaminouracil and 3-[3-(benzoyloxymethyl)oxazol-5-yl]acrylic acid, the requisite intermediate was prepared, as described for Example 41. The product was treated with sodium hydride, followed by methyl iodide in THF to provide the desired product.

MP: 165° C.; ¹H-NMR (DMSO-d₆): δ 0.85 (m, 6H), 1.59 (m, 2H), 1.72 (m, 2H), 3.85 (t, 2H), 3.98 (t, 2H), 4.03 (s, 3H), 5.50 (s, 2H), 7.30 (s, 1H), 7.57 (m, 3H), 7.59 (d, 2H, J=8Hz), 8.03 (d, 2H, J=8Hz).

EXAMPLE 51 Preparation of Compound AS53

To a solution of 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (3 mmol, Example 1) in 1,4-dioxane at room temperature was added 4-(dimethylaminophenyl)isocyanate (3.2 mmol). The mixture was stirred overnight at room temperature, quenched by the addition of water, and the precipitated product collected by filtration. Purification was achieved by column chromatography on silica gel.

MP: 266-268° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.50 (m, 2H), 1.60 (m, 2H), 2.80 (s, 6H), 3.83 (m, 2H), 3.98 (m, 2H), 4.10 (s, 3H), 6.69 (d, 11H, J=8.0 Hz), 6.94 (d, 1H, J=8.0 Hz), 7.1 (s, 1H), 7.27 (d, 2H, J=8.0 Hz), 8.64 (s, 1H), 8.98 (s, 1H).

EXAMPLE 52 Preparation of Compound AS54

Using 3-chlorophenylisocyanate and 1,3-dipropyl-8-(3-amino-1-methyl-pyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.50 (m, 2H), 1.60 (m, 2H), 3.83 (m, 2H), 3.98 (m, 2H), 4.10 (s, 3H), 7.01 (m, 1H), 7.19 (s, 1H), 7.30 (m, 2H), 7.70 (s, 1H), 9.03 (s, 1H), 9.15 (s, 1H), 14.0 (s, 1H).

EXAMPLE 53 Preparation of Compound AS55

Using 3-(methoxy)phenylisocyanate and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

MP: >300° C.; ¹H-NMR (DMSO-d₆): δ 0.87 (m, 6H), 1.50 (m, 2H), 1.60 (m, 2H), 3.82 (s, 3H), 3.86 (m, 2H), 3.98 (m,2H), 4.10 (s, 3H), 6.54 (d, 1H, J=8.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 7.10 (s, 1H), 7.24 (m, 2H), 8.90 (s, 1H), 9.07 (s, 1H), 14.0 (s, 1H,

EXAMPLE 54 Preparation of Compound AS49

Using 4-(methoxy)phenylisocyanate and 1,3-dipropyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (Example 1, Compound AS3).

Yield: 98% MP: >300° C.; 1H NMR (DMSO-d₆): δ 0.80 (m, 6H); 1.62 (m, 2H); 1.70 (m, 2H); 3.68 (s, 3H); 3.75 (m, 2H); 4.02 (m, 2H); 4.22 (s, 3H); 7.00 (d, 2H, J=8.00 Hz); 7.25 (s, 1H); 7.32 (d, 2H, J=8.00 Hz); 8.82 (s, 1H); 8.95 (S, 1H); 14.01 (s, 1H).

EXAMPLE 55 Preparation of Compound AS1

To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol (10 mL) was added an equimoiar amount of 1-methyl-1H-pyrazole-3,5-dicarboxylic acid 5-ethyl ester and DCI (2.21 mmol). The reaction mixture was stirred at room temperature for 4-5 h with monitoring by TLC. At completion, the reaction mixture was concentrated in vacuo and water added. The intermediate amide precipitated and was collected by filtration. The solid thus collected was dissolved in methanol (10 mL), 2.5 N NaOH (15 mL) added, and the mixture heated to 70-80° C. for 12 hours. After removal of the methanol, the residue was taken up in water, acidified to pH 4-5 with HCl, and the resultant precipitate collected by filtration. The desired product was purified by flash chromatography on silica gel, eluting with ethyl acetate/petroleum ether.

Yield: 40%; MP: >300° C.; 1H NMR (DMSO-d₆): δ 0.93 (m, 6H); 1.58 (m, 2H), 1.75 (m, 2H); 3.88 (m, 2H); 3.98 (m, 2H); 4.01 (s, 3H); 7.43 (s,1H); 13.60 (bs, 2H).

EXAMPLE 56 Preparation of Compound AS91

Using 4-(sec-butyl)aniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 36%; MP: 240-242° C.; 1H NMR (DMSO-d₆): δ 0.74 (t, 3H, J=8.00); 0.85 (m, 9H); 1.15 (d, 3H, J=8.00); 1.51 (m, 2H); 1.55 (m, 2H); 3.86 (m, 2H); 4.00 (m, 2H); 4.06 (s, 3H); 4.74 (s, 2H); 6.50 (s, 1H); 7.12 (d, 2H, J=8.00); 7.52 (d, 2H, J=8.00); 10.02 (s, 1H); 13.93 (s, 1H).

EXAMPLE 57 Preparation of Compound AS92

Using 4-(methyl)aniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 38%; MP: 256-257° C.; 1H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.56 (m, 2H); 1.73 (m, 2H); 2.24 (s, 3H); 3.84 (m, 2H); 3.94 (m, 2H); 4.05 (s, 3H); 4.74 (s, 2H); 6.51 (s, 1H); 7.12 (d, 2H, J=8.10); 7.50 (d, 2H, J=8.15); 10.01 (s, 1H); 13.94 (s, 1H).

EXAMPLE 58 Preparation of Compound AS93

Using 4-(N-morpholino)aniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 46%; MP: 296-298° C.; 1H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.57 (m, 2H); 1.75 (m, 2H); 3.03 (m, 4H); 3.71 (m, 4H); 3.74 (m, 2H); 3.85 (m, 2H); 4.03 (s, 3H); 4.71 (s, 2H); 6.46 (s, 1H); 6.89 (d, 2H, J=8.27); 7.48 (d, 2H, J=8.22); 9.89 (s, 1H); 13.86 (bs, 1H).

EXAMPLE 59 Preparation of Compound AS94

Using ethyl 4-(amino)benzoate and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 48%; MP: 294° C.; 1H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.30 (m, 3H, J=8.00); 1.58 (m, 2H); 1.62 (m, 2H); 3.85 (m, 2H); 3.96 (m, 2H); 4.03 (s, 3H); 4.24 (q, 2H, J=8.00); 4.80 (s, 2H); 6.44 (s, 1H); 7.77 (d, 2H, J=8.00); 7.92 (d, 2H, J=8.00); 10.46 (s, 1H); 13.92 (s, 1H).

EXAMPLE 60 Preparation of Compound AS95

Using 4-(amino)benzoic acid and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 38%; MP: >300° C.; 1H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.56 (m, 2H); 1.73 (m, 2H); 3.86 (m, 2H); 3.98 (m, 2H); 4.06 (s, 3H); 4.81 (s, 2H); 6.49 (s, 1H); 7.74 (d, 2H, J=8.70); 7.80 (d, 2H, J=8.58); 10.44 (s, 1H); 13.92 (s, 1H).

EXAMPLE 61 Preparation of Compound AS99

Using 3,4-dimethylaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 65%; MP: 264-265° C.; 1H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.57 (m, 2H); 1.73 (m, 2H); 2.16 (m, 6H); 3.83 (m, 2H); 3.98 (m, 2H); 4.06 (s, 3H); 4.73 (s, 2H); 6.51 (s, 1H); 7.31 (m, 1H); 7.34 (m, 2H); 9.93 (s, 1H); 13.90 (s, 1H).

EXAMPLE 62 Preparation of Compound AS100

Using 3,4-dichloroaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 55%; MP: 258° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.57 (m, 2H); 1.72 (m, 2H); 3.84 (m, 2H); 4.00 (m, 2H); 4.06 (s, 3H); 4.78 (s, 2H); 6.52 (s, 1H); 7.57 (s, 2H); 8.02 (s, 1H); 10.42 (s, 1H); 13.94 (s, 1H).

EXAMPLE 63 Preparation of Compound AS101

Using 3,4-dimethoxyaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 60%; MP: 291-293° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.59 (m, 2H); 1.77 (m, 2H); 3.71 (m, 6H); 3.87 (m, 2H); 4.00 (m, 2H); 4.07 (s, 3H); 4.73 (s, 2H); 6.51 (s, 1H); 6.89 (m, 1H); 7.14 (m, 1H); 7.33 (m, 1H); 9.95 (s, 1H); 13.97 (s, 1H).

EXAMPLE 64 Preparation of Compound AS89

Using 4-aminopyridine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 35%; MP: 248-251° C.; ¹H NMR (DMSO-d₆): 60.9 (m, 6H); 1.55 (m, 2H); 1.67 (m, 2H); 3.89 (m, 2H); 4.00 (m, 2H); 4.05 (s, 3H); 4.82 (s, 2H); 6.44 (s, 1H); 7.64 (d, 2H, J=8.80); 7.93 (d, 2H, J=8.92); 10.43 (s, 1H); 13.95 (bs, 1H).

EXAMPLE 65 Preparation of AS70

Using N-phenyl-piperazine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 38%; MP: 273-274° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.69 (m, 2H); 1.71 (m, 2H); 3.18 (m, 4H); 3.57 (m, 4H); 3.86 (m, 2H); 4.00 (m, 2H); 4.05 (s, 2H); 6.46 (s, 1H); 6.81 (m, 1H); 6.96 (d, 2H, J=8.00); 7.21 (t, 2H, J=8.00); 13.92 (s, 1H).

EXAMPLE 66 Preparation of AS72

Using N-(4-fluorophenyl)-piperazine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 40%; MP: 235-237° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.57 (m, 2H); 1.74 (m, 2H); 3.09 (m, 4H); 3.84 (m, 2H); 3.95 (m, 2H); 4.05 (s, 3H); 4.92 (s, 2H); 6.46 (s, 1H); 7.01 (m, 4H); 13.92 (s, 1H).

EXAMPLE 67 Preparation of AS87

Using N-methyl-piperazine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 56%; MP: 192-194° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.06 (m, 2H); 1.20 (m, 2H); 2.39 (m, 4H); 3.39 (m, 4H); 3.75 (m, 2H); 3.90 (s, 3H); 4.12 (m, 2H); 4.04 (s, 3H); 4.85 (s, 2H); 6.92 (s, 1H); 13.92 (s, 1H).

EXAMPLE 68 Preparation of AS90

Using N-benzyl-piperazine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.

Yield: 32%; MP: 236-237° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.08 (m, 2H); 1.12 (m, 2H); 2.39 (m, 4H); 3.39 (m, 4H); 3.50 (s, 2H); 3.86 (m, 2H); 4.00 (m, 2H), 4.04 (s, 3H); 4.85 (s, 2H); 6.42 (s, 1H); 7.31 (m, 5H); 13.92 (s, 1H).

EXAMPLE 69 Preparation of AS96

To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.

Condensation of 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (0.5 mmol) and N-phenyl-piperazine (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

Yield: 27%; MP: 289-290° C.; ¹H NMR (DMSO-d₆): δ 3.17 (m, 4H); 3.57 (m, 4H); 4.05 (s, 3H); 4.51 (m, 2H); 4.64 (m, 2H); 4.93 (s, 2H); 5.11 (m, 4H); 5.89 (m, 2H); 6.46 (s, 1H); 6.81 (m, 1H); 6.96 (d, 2H, J=8.13); 7.23 (t, 2H, J=8.00); 14.00 (s, 1H).

EXAMPLE 70 Preparation of AS105

Using N-(pyridin-2-yl)-piperazine and 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 69), according to the method described in Example 69.

EXAMPLE 71 Preparation of AS106

Using N-(pyrimidin-2-yl)-piperazine and 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 69), according to the method described in Example 69.

EXAMPLE 72 Preparation of AS109

Using N-(4-sulfonamidophenyl)-piperazine and 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 69), according to the method described in Example 69.

EXAMPLE 73 Preparation of ethyl (5-(methoxycarbonyl)-isoxazol-3-yl)oxyacetate

To a solution of methyl 3-hydroxy-isoxazole-5-carboxylate (7.14 mmol) in acetone (30 mL), was added potassium carbonate (1.2 g, 8.6 mmol) and ethyl bromoacetate (8.6 mmol). The reaction mixture was heated at reflux for 2 h, monitoring by TLC. At completion, acetone was removed in vacuo and the residue partitioned between water and ethyl acetate (50 mL). The organic layer was dried (MgSO₄), filtered, and evaporated to afford the desired intermediate.

Yield: 81%; MP: 66-67° C.; ¹H NMR (CDCl₃): δ 1.30 (t, 3H, J=7.22); 3.96 (s, 3H); 4.27 (q, 2H, J=7.21); 4.87 (s, 2H); 6.65 (s, 1H).

EXAMPLE 74 Preparation of (5-carboxyisoxazol-3-yl)oxyacetic Acid

A solution of ethyl (5-(methoxycarbonyl)isoxazol-3-yl)oxyacetate (4 mmol, Example 73) in methanol (60 mL) and 5% aqueous NaOH is heated at reflux for 1 hour. At the end of this time, the methanol is removed, the residue diluted with additional water, and acidified to pH=4 with hydrochloric acid. The resulting precipitate is collected by filtration, washed with cold water, and dried.

Yield: 90%; MP: >300° C.; ¹H NMR (DMSO-d₆): 0 4.71 (s, 2H); 6.22 (s, 1H); 11.30 (bs, 1H); 14.75 (bs, 1H).

EXAMPLE 75 Preparation of ethyl (5-carboxyisoxazol-3-yl)oxyacetate

(5-Carboxyisoxazol-3-yl)oxyacetic acid (4.0 mmol, Example 74) is dissolved in ethanol (50 mL), to which is added a catalytic amount of p-toluenesulfonic acid (100 mg). After stirring overnight at room temperature, the ethanol was removed and the residue was recrystallized from ethanol/water.

Yield: 70%; MP: 145-150° C.; ¹H NMR (CDCl₃): [1.40 (t, 3H, J=7.18); 4.20 (q, 2H, J=7.21); 4.90 (s, 2H); 6.75 (s, 1H); 11.35 (bs, 1H).

EXAMPLE 76 Preparation of AS74

To a solution of ethyl (5-carboxyisoxazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid.

Condensation of 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

EXAMPLE 77 Preparation of AS76

Using 3,4-dimethoxyaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid (Example 76), according to the method described in Example 76.

Yield: 36%; MP: 253-255° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.55 (m, 2H); 1.70 (m, 2H); 3.72 (s, 6H); 3.85 (m, 2H); 3.97 (m, 2H); 4.90 (s, 2H); 6.90 (m, 2H); 7.12 (m, 1H); 7.30 (s, 1H); 10.10 (bs, 1H); 14.60 (bs, 1H).

EXAMPLE 78 Preparation of AS73

Using 4-fluoroaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid (Example 76), according to the method described in Example 76.

Yield: 28%; MP: 287° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.55 (m, 2H); 1.70 (m, 2H); 3.85 (m, 2H); 3.97 (m, 2H); 4.93 (s, 2H); 6.90 (s, 1H); 7.18 (m, 2H); 7.62 (m, 2H); 10.29 (bs, 1H); 14.60 (bs, 1H).

EXAMPLE 79 Preparation of AS75

Using 4-methoxyaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-isoxazol-3-yloxy]acetic acid (Example 76), according to the method described in Example 76.

Yield: 38%; MP: 285-287° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.59 (m, 2H); 1.68 (m, 2H); 3.71 (s, 3H); 3.85 (m, 2H); 3.97 (m, 2H); 4.90 (s, 2H); 6.91 (m, 3H); 7.50 (m, 2H); 10.09 (s, 1H); 14.56 (bs, 1H).

EXAMPLE 80 Preparation of 2-bromo-N-(4-iodophenyl)acetamide

To a solution of 4-iodoaniline (14.5 mmol) in anhydrous dichloromethane at 0° C. was added a-bromo-acetylbromide (1.4 mL) and triethylamine (15 mmol). The mixture was warmed to room temperature, stirred for 1 h, the solvent removed, and residue dissolved in 5% hydrochloric acid. The aqueous solution was extracted with ethyl acetate, the organic layer washed with brine, dried (Na2SO4), filtered, and evaporated. The solid residue was purified by recrystallization form ethyl acetate to afford the desired intermediate.

Yield: 60%; MP: 185° C.; ¹H NMR (CDCl₃): δ 4.93 (s, 2H); 8.24 (d, 2H, J=8.00); 8.58 (d, 2H, J=8.00); 9.02 (bs,1H).

EXAMPLE 81 Preparation of 1,3-dipropyl-8-(6-hydroxy-pyridazin-3-yl)-xanthine

To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol was added an equimolar amount of 6-hydroxy-pyridazine-3-carboxylic acid, followed by a slight excess of DCl ((N-(3-(dimethylamino)propyl)-N′ethylcarbodiimide hydrochloride). The mixture was stirred at room temperature for 4-5 hours until complete by TLC. Water was then added and the precipitate removed by filtration. The solid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was acidified to pH=5 with 10% hydrochloric acid and the precipitated product collected by filtration.

Yield: 30%; MP: 216° C.; ¹H NMR (DMSO-d₆): δ 0.87 (m, 6H); 1.65 (m, 4H); 3.5 (bs, 1H), 3.84 (m, 2H); 3.97 (m, 2H); 6.99 (d, 1H); 8.04 (d, 1H); 13.32 (bs, 1H).

EXAMPLE 82 Preparation of AS85

To a solution of 1,3-dipropyl-8-(6-hydroxy-pyridazin-3-yl)-xanthine (0.20 mmol, Example 81) in anhydrous dimethylformamide (10 mL) was added an equimolar amount of triethylamine. The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of 2-bromo-N-(4-iodophenyl)acetamide (0.20 mmol, Example 80). After stirring at room temperature overnight, the solvent was distilled off, the residue was taken up in cold water, and the precipitated product collected by filtration. The product was further purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.

Yield: 28%; MP: 310° C.; ¹H NMR (DMSO-d₆): δ 0.86 (m, 6H); 1.55 (m, 2H); 1.76 (m, 2H); 3.80 (m, 2H); 4.03 (m, 2H); 5.58 (s, 2H); 7.04 (d, 1H, J=9.92); 7.37 (d, 2H, J=8.64); 7.65 (d, 2H, J=8.55); 8.09 (d, 1H, J=10.01); 10.45 (s,1H); 13.30 (bs,1H).

EXAMPLE 83 Preparation of AS103

To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol was added an equimolar amount of 2-hydroxy-pyridine-5-carboxylic acid, followed by a slight excess of DCl ((N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride). The mixture was stirred at room temperature for 4-5 hours until complete by TLC. Water was then added and the precipitate removed by filtration. The solid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was acidified to pH=5 with 10% hydrochloric acid and the precipitated product collected by filtration.

Yield: 25%; MP: >300° C.; ¹H NMR (DMSO-d₆): δ 0.88 (m, 6H); 1.60 (m, 4H);3.84 (bs,1H); 3.84 (m, 2H); 3.97 (m, 2H); 6.47 (d, 1H); 8.08 (m,1H); 8.20 (m, 1H); 13.30 (bs, 1H).

EXAMPLE 84 Preparation of AS81

To a solution of 1,3-dipropyl-8-(2-hydroxy-pyridin-5-yl)-xanthine (0.20 mmol, Example 81) in anhydrous dimethylformamide (10 mL) was added an equimolar amount of triethylamine. The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of 2-bromo-N-(4-iodophenyl)acetamide (0.20 mmol, Example 80). After stirring at room temperature overnight, the solvent was distilled off, the residue was taken up in cold water, and the precipitated product collected by filtration. The product was further purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol.

Yield: 25%; MP: 293° C.; ¹H NMR (DMSO-d₆): δ 0.86 (m, 6H); 1.55 (m, 2H); 1.76 (m, 2H); 3.80 (m, 2H); 3.89 (m, 2H); 5.21 (s, 2H); 6.37 (d, 1H, J=9.46); 7.45)d,

EXAMPLE 85 Preparation of Compound AS68a

To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.

Condensation of 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCI (1.12 minoR) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.

MP: 288-289° C.; 1H-NMR (DMSO-d₆): δ 2.50 (s, 3H), 4.51 (d, 2H), 4.62 (d, 2H), 4.72 (s, 2H), 5.07 (d, 1H), 5.10 (d, 1H), 5.15 (s, 1H), 5.18 (d, 1H), 5.90 (m, 2H), 5.98 (s, 2H), 6.51 (s, 1H), 6.87 (d, 1H, J=8.44Hz), 7.01 (d, 1H), 7.32 (s, 1H), 10.01 (s, 1H); 14.01 (bs, 1H).

Preparation of Radioligand Compounds

The compounds can be labeled with any suitable radiolabel. Examples of suitable radiolabels include tritium (³H) and carbon radioisotopes (e.g. ¹⁴C), but any substantially non-toxic radiolabel commonly used in pharmacokinetic studies can be used. Means for incorporating radiolabels onto organic compounds are well known to those of skill in the art.

When the compounds are synthesized from a starting 1,3-dialkyl-5,6-diaminouracil, incorporation of a radiolabel is fairly straightforward. For example, the diaminouracil can be obtained containing a suitable radiolabel. As an alternate, the diaminouracil can be obtained with one or more sites of unsaturation in an attached substituent (e.g. iso-propylene in place of isopropyl). The unsaturated double bond can then be reacted with tritium in the presence a suitable catalyst, for example, palladium on charcoal or other known hydrogenation catalysts. Using the radiolabelled diaminouracil and following the methods of synthesis herein described will result in the corresponding radiolabelled compound.

It has been established by the inventors, as well as known by those skilled in the art, that ³H and ¹⁴C labeled compounds have binding affinity to the adenosine A₁, A_(2A), A_(2B), and A₃ A_(2B), and A₃ receptor subtypes comparable to that of corresponding non-labeled forms.

EXAMPLE 86 Preparation of Radioligand of Compound AS16

A solution of 1,3-diallyl-5,6-diaminouracil (0.7 g, 0.003 mol), 1-methyl-3-(benzyloxycarbonylamino)-pyrazole-5-carboxylic acid (0.8 g, 0.003 mol), and EDCl (0.6 g, 0.003 mol) in 50 mL of CH₃OH is stirred at room temperature for two hours. Excess CH₃OH is evaporated in vacuo to give a yellow solid that is collected by filtration and washed with H₂O to give the amide intermediate.

A mixture of the amide intermediate and 30 mL of 2.5 N NaOH is warmed to 70-80° C. for three hours. The clear aqueous solution is cooled and acidified to pH 5 with concentrated HCl. The white precipitate that forms is collected by filtration and washed with H₂O to afford the desired 1,3-diallyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine, which is recrystallized from CH₃OH. A solution of 4-(benzyloxy)phenylacetic acid (0.196 mmol) in 3 mL of thionyl chloride is stirred at 70° C. for four hours, then excess thionyl chloride removed in a nitrogen stream.

A solution of 1,3-diallyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine (0.151 mmol, Example 1) and 0.04 mL of anhydrous triethyl amine in 10 mL of CH₂Cl₂: CH₃OH (1:1) is added and the mixture is stirred at room temperature for 24 hours, monitoring by TLC. At completion, the solvent is evaporated, the residue is dissolved in ethyl acetate, and the solution washed with saturated aqueous NaHCO₃ and brine. The organic layer is dried (Na₂SO₄), filtered, and evaporated in vacuo. The desired intermediate is purified by column chromatography on silica gel.

To a suspension of 10% Pd/C (5 mg) in CH₃CH₂OH (10 mL) is added a solution of 1,3-diallyl-8-(3-(2-(4-(benzyloxy)phenyl)acetylamino-)-1-methylpyrazol-5-yl)xanthine in CH₃CH₂OH (3 mL). The mixture is evacuated and charged with tritium gas to 50 psi, then shaken at room temperature for 16 hours. The mixture is evacuated, the solution filtered to remove catalyst, and the solution evaporated in vacuo. The residue is purified by column chromatography to provide the desired tritiated analogue, identical chromatographically to Example 7.

EXAMPLE 87 Preparation of Radioligand of Compound AS68

To a solution of ethyl (5-[¹⁴C]-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) is added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture is stirred at room temperature for two hours, the solvent is then removed in vacuo, water is added, and the solid that forms is collected by filtration and washed with additional cold water. The intermediate amide is heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-8-[¹⁴C]-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.

Condensation of 2-[5-(1,3-dipropyl-[¹⁴C]-8-[xanthin-8-yl]-1-methylpyrazol-3-yloxy]acetic acid (0.5 mmol) and 3,4-methylenedioxyaniline (1.3 mmol) in the presence of EDCI (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide affords the desired [¹⁴C]-labeled product, identical chromatographically with Example 39.

Preparation of Fluorescently Labeled Compounds

As with the radiolabelled compounds, the synthesis of fluorescently labeled compounds is relatively straightforward. Chemical bonding of fluorescent labels, with or without a linking or tethering group, to oligomeric compounds, is well known in the art (see for example: Hill, J. J. and Royer, C. A., Methods Enzymol., 1997, 278, 390-416; and Amann et al., Microbiol. Rev., 1997, 20, 191-200). Typically, the fluorescent label is attached via a covalent bond using a tethering moiety. Additional techniques and uses of fluorescently labeled compounds are disclosed in U.S. Pat. No. 6,127,124 to Leeds et al., incorporated herein by reference.

Utility

The compounds of the present invention can be used in vitro for scientific studies requiring highly selective A_(2B) radioligands. For example, the present inventive 8-heteroaryl xanthine derivatives may be used to probe adenosine receptors in order to isolate or characterize the receptors.

Additionally, the compounds of the present invention can be used in vivo for treating diseases induced by activation of the adenosine A_(2B) receptor and inflammatory diseases involving degranulation of mast cells including asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, allergic rhinitis, allergic dermatitis and bee sting; impaired sensitivity to insulin including Type 2 diabetes or non-insulin dependent diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis including solid tumors and angiogenic retinopathies; and apnea of preterm infants.

Furthermore, following the teachings of Belardinelli, the compounds of the present invention may be used for inhibiting cell proliferation in cells that express the A_(2B) adenosine receptor including human retinal endothelial cells (HREC). Such uses include treatment for chronic and acute inflammatory diseases involving degranulation of mast cells including asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, allergic rhinitis, allergic dermatitis and bee sting; impaired sensitivity to insulin including Type 2 diabetes or non-insulin dependent diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis including solid tumors and angiogenic retinopathies; and apnea of preterm infants; myocardial reperfusion injury, inflammatory bowel disease, and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS) and lupus erythematosis.

Similarly, the compounds can be used in a method for the treatment of diseases involving microvascular abnormalities of the retina that are mediated by adenosine A_(2B) receptors. Such diseases include, but are not limited to, retinopathy, prematurity, macular degeneration, and diabetic retinopathy.

The compounds of the present invention can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical, inhalation or subcutaneous routes. Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets or may be incorporated directly with the food of the patient's diet.

For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol.

Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

It is desirable that any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active compound of the present invention that is further adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form is preferably sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium such as, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.

The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and celatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount of the appropriate solvent with various other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which yield a powder of the active compound plus any additional desired ingredient.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Examples of useful dermatological compositions which, can be used to deliver the compounds of present invention to the skin are known in the art, for example, as described in U.S. Pat. Nos. 4,608,392, 4,992,478, 4,559,157 and 4,820,508.

Useful dosages of the compounds of the present invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the: extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of the present invention in a liquid composition, such as a lotion, will be from about 0.01-25 wt-%, preferably from about 0.1-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0. 1-5 wt-%, preferably about 0.5-2.5 wt %.

The amount of the compound or an active salt or derivative required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the administering physician or clinician. In general, a suitable dose will be in the range of from about 0.001 mg/kg/day to about 20 mg/kg/day. For example, a dosage may be from 0.002 mg/kg/day to about 10 mg/kg of body weight per day, preferably in the range of 0.0l mg/kg/day to 1 mg/kg/day, and most preferably in the range of 0.1 mg/kg/day to 5 mg/kg/day.

The compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 μg, conveniently 10 to 750 μg, most conveniently, 50 to 500 μg of active ingredient per unit dosage form.

The compounds of the invention can be administered by inhalation from an inhaler, insufflator, atomizer or pressurized pack or other means of delivering an aerosol spray. Pressurized packs may use a suitable propellant such as carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a value to deliver a metered amount. The inhalers, insufflators, and atomizers are fully described in pharmaceutical reference books such as Remington's Pharmaceutical Sciences 18th edition (1990) Mack Publishing Co., Easton, Pa.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. Dosages above or below the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary.

When used in the treatment of treatment for ischemic injury to retinal vessels the compounds of the present invention are preferably formulated in eyedrops suitable for topical application.

Biological Assays

All synthesized compounds have been tested for their affinity to human A1, A_(2A), A_(2B) and A₃ adenosine receptors expressed in Chinese Hamster Ovary cells (CHO) (A₁, A_(2A) and A₃) and HEK 293 cells (A_(2B)) using cell binding assay techniques known in the art.

The cells were grown adherently and maintained in Dulbecco's modified Eagle's medium with nutrient mixture F12 without nucleosides at 37° C. in 5% CO_(2/95)% air. The cells were washed with phosphate-buffered saline and scraped off flasks in ice cold hypotonic buffer (5 nM Tris HCl, 2 mM EDTA, pH 7.4). The cell suspension was homogenized with a Polytron and the homogenate was centrifuged for 30 minutes at 48,000 g. The resultant membrane pellet was re-suspended in 50 mM Tris HCl buffer at pH 7.4 for A₁ adenosine receptors; in 50 mM Tris HCl 10 mM MgCl, at pH 7.4 for A_(2A) adenosine receptors; in 50 mM Tris HCl, 10 mM MgCl₂, 1 mM EDTA, at pH 7.4 for A₃ adenosine receptors and were utilized for binding assays.

HEK 293 cells transfected with the human recombinant A_(2B) adenosine receptor were obtained from Receptor Biology, Inc. (Beltsville, Md. USA).

Binding of [³H]-DPCPX to CHO cells transfected with the human recombinant A₁ adenosine receptor was performed according to the method previously described by Klotz et al. 1985. Displacement experiments were performed for 120 minutes at 25° C. in 200 μl of buffer containing 1 nM ³H]-DPCPX 20 μl of diluted membranes (50 μg of protein/assay) and at least 6 to 8 different concentrations of examined compounds. Non-specific binding was determined in the presence of 10 μM of CHA and this is always less than 10% of the total binding.

Binding of [³H]ZM-241385 to CHO cells transfected with the human recombinant A_(2A) adenosine receptors (50 μg of protein/assay) was performed according to Varani et al., 2000. In competition studies, at least 6-8 different concentrations of compounds were used and non-specific binding was determined in the presence of 1 μM ZM-241385 with an incubation time of 60 minutes at 25° C.

Binding of 1 [³H]-DPCPX to HEK 293 cells transfected with the human recombinant A_(2B) adenosine receptors was performed according to the method described by Varani et al., 2000. In particular, assays were carried out for 60 minutes at 25° C. in 100 μl of 50 nM Tris HCl buffer, 10 nM MgCl₂, 1 mM EDTA, 0.1 mM benzamidine pH 7.4, 2 IU/ml adenosine deaminase containing 40 nM [³H]-DPCPX, diluted membranes (20 μg of protein/assay) and at least 6-8 different concentration of tested compounds. Non-specific binding was determined in the presence of 100 μM of NECA and was always less than 30% of the total binding.

Binding of [³H]-MRE3008-F20 to CHO cells transfected with the human recombinant A₃ adenosine receptors was performed according to Varani et al., 2000. Competition experiments were carried out in duplicate in a final volume of 250 μl in test tubes containing 1 nM [³H]-MRE3008-F20, 50 mM Tris HCl buffer, 10 nM MgCl₂, pH 7.4 and 100 μl of diluted membranes (50 μg of protein/assay) and at least 6-8 different concentrations of examined ligands for 120 minutes at 4° C. Non-specific binding was defined as binding in the presence of 1 μM [³H]-MRE3008-F20 and was about 25% of total binding.

Bound and free radioactivity portions were separated by filtering the assay mixture through Whatman GF/B glass-fiber filters using a Micro-Mate 196 cell harvester (Packard Instrument Company). The filter bound radioactivity was counted on Top Count (efficiency 57%) with Micro-Scint 20. The protein concentration was determined according to a Bio-Rad method (Bradford, 1976) with bovine albumin as reference standard.

Measurement of cyclic AMP (CAMP) levels in CHO cells transfected with human A_(2B) adenosine receptors was performed in the following manner. CHO cells transfected with human A₂B adenosine receptors were washed with phosphate-buffered saline, diluted tripsine and centrifuged for 10 minutes at 200 g. The pellet containing the CHO cells (1.times.10⁶ cells/assay) was suspended in 0.5 ml of incubation mixture (mM): 15 mM NaCl, 0.27 mM KC1, 0.037 mM NaH₂PO₄, 0.1 mM MgSO₄, 0.1 CaCl₂, 0.01 mM Hepes, 1 mM MgCl, 0.5 mM glucose, pH 7.4 at 37° C., 2 IU/ml adenosine deaminase and 4-(3-butoxy-4methoxybenzyl)-2-imidazolidinone (Ro 20-1724) as phosphodiesterase inhibitor and preincubated for 10 minutes in a shaking bath at 37° C.

The potencies of antagonists studied were determined by antagonism of NECA (100 nM)-induced stimulation of cAMP levels. The reaction was terminated by the addition of cold 6% thrichloroacetic acid (TCA). The TCA suspension was centrifuged at 2000 g for 10 minutes at 4° C. and the supernatant was extracted four times with water saturated diethyl ether. The final aqueous, solution was tested for cAMP levels by a competition protein binding assay. Samples of cAMP standard (0-10 pmoles) were added to each test tube containing the incubation buffer (trizma base 0.1 M, aminophylline 8.0 mM, 2-mercaptoethanol 6.0 mM, pH 7.4) and [H³]-cAMP in a total volume of 0.5 ml. The binding protein previously prepared from beef adrenals, was added to the samples previously incubated at 4° C. for 150 minutes, and after the addition of charcoal were centrifuged at 2000 g for 10 minutes. The clear supernatant was counted in a Beckman scintillation counter.

Data Analysis

The filter bound radioactivity was counted on a Top Count brand Microplate Scintillation Counter (efficiency 57%) with Micro-Scint 20. The protein concentration was determined according to a Bio-Rad method (Bradford. 1976) with bovine albumin as a standard reference. Inhibitory binding constant K_(i) values were calculated from those of IC₅₀ according to the Cheng and Prusoff equation (Cheng and Prusoff, 1973): K _(i) =IC ₅₀/(1+[C*]/K _(D)*),

where [C*] is the concentration of the radioligand and K_(D)* is its dissociation constant. The weighted non-linear least-squares curve fitting program LIGAND (Munson & Rodboard, 1980) was used for computer analysis of saturation and inhibition experiments. All data (K_(i) and IC₅₀) are expressed as geometric means with 95% confidence intervals.

Results and Discussion

Binding results, expressed as K_(i) for the synthesized compounds AS3 to AS69 are reported in Table 1. A binding of greater than 1,000 nM (1.0 μM) is indicated when no appreciable binding was measured. As is seen in Table 1, the compounds of the present invention present a wide range of binding affinities hence making selection of antagonism for various adenosine receptor subtypes possible. For example, a compound such as AS68 is a highly potent A₂₈ antagonist and retains significant A₁ antagonism. Compounds such as AS28 provide less A_(2B) affinity but are totally selective with no appreciable binding to the other adenosine receptor subtypes.

The Compound AS68 has the highest measured affinity for the human A_(2B) receptors (K₁=5.5 nM), binding to adenosine A₁ receptors (K_(i)=200 nM) but appears to show little or no affinity to human A^(2A) and A₃ adenosine receptors subtypes. The compounds AS29, AS39, AS57, AS64 and AS65 have good affinity for the human A_(2B) receptors with an affinity value in the nanomolar range (K_(i)=9-20 nM). Other compounds such as AS11, AS27, AS28, AS35 and AS54 showed a K_(i) value in the nanomolar range (K_(i)=28-39 nM) for A_(2B) receptors. Compounds AS13, AS15, AS16 and AS17 show affinity in nanomolar range (K_(i)=56-103 nM) to the human A_(2B) receptor, with no appreciable affinity for the other adenosine receptor subtypes.

TABLE 1 Binding Affinites to Adenosine Receptors Ki (nM) [³H]MRE3008F20 binding to human A₃ [³H]DPCPX binding to [³H]ZM241385 binding to [³H]DPCPX binding to receptors Compound human A₁ receptors human A_(2A) receptors human A₂₈ receptors expressed in CHO Number expressed in CHO cells expensed in CHO cells expressed in HEK293 cells cells AS3 201(172-236) >1000  235(209-264) >1000 AS11 900(811-996) >1000 35(27-45) >1000 AS12 >1000 >1000 >1000 >1000 AS13 >1000 >1000  96(80-114) >1000 AS14 >1000 >1000 >1000 >1000 AS15 >1000 >1000 78(63-96) >1000 AS16 >1000 >1000 56(42-77) >1000 AS17 >1000 >1000 103(79-136) >1000 AS18 >1000 >1000 >1000 >1000 AS19 >1000 >1000 >1000 >1000 AS21 >1000 >1000 >1000 >1000 AS22 200(166-240) >1000 88(84-92) >1000 AS23 850(762-946) >1000 100(83-120) >1000 AS24  4481(3650-5501) >1000  160(142-179) >1000 AS25  3227(2799-3720) >1000 50(41-60) >1000 AS26 >1000 >1000  1628(1374-1930) >1000 AS27 520(484-558) >1000 28(23-33) >1000 AS28 >1000 >1000 38(33-43) >1000 AS29 56(47-67)  >1000 13(11-16) >1000 AS30 100(83-120)  >1000  90(73-110) >1000 AS31 163(137-193) >1000  111(100-124) >1000 AS32 746(659-843) >1000  190(172-209) >1000 AS43  1898(1723-2091) >1000  130(113-150) >1000 AS44 >1000 >1000 >1000 >1000 AS56  1793(1460-2201) 2433(1675-3533) 100(83-120) >1000 AS57 566(516-621) 1249(856-1822)  18(12-27) >1000 AS58 >1000 1755(1343-2292)  342(274-426) >1000 AS8 >1000 >1000 >1000 >1000 AS9 >1000 >1000 >1000 >1000 AS10 548(464-648) >1000  2065(1866-2284) >1000 AS38 >1000 >1000  175(134-229) >1000 AS40 >1000 >1000  569(506-640) >1000 AS7 122(84-177)  >1000  342(274-426) >1000 AS36 >1000 >1000 >1000 >1000 AS33 >1000 >1000 >1000 >1000 AS59 >1000 >1000  1012(819-1250) >1000 AS64 65(48-86)  >1000 12(7-21) >1000 AS65 150(132-170) >1000 20(16-25) >1000 AS68 200(180-226) >1000  5.5(4.6-6.5) >1000 AS69 >1000 >1000 86(77-96) >1000 AS66 467(400-546) >1000  303(260-352) >1000 AS67  2427(2067-2850) >1000 132(98-178) >1000 AS37 140(123-159) >1000 58(45-74) >1000 AS35 55(46-65)  >1000 34(26-46) >1000 AS60 168(140-201) >1000  93(82-105) >1000 AS61 181(127-258) >1000  185(163-210) >1000 AS62 72(45-114) >1000  207(162-265) >1000 AS63 49(34-72)  >1000  66(38-116) >1000 AS4 >1000 >1000 >1000 >1000 AS20 >1000 >1000 >1000 >1000 AS53  2410(1760-3301) >1000 59(44-81) >1000 AS54 448(365-550) >1000 39(33-46) >1000 AS55  1993(1658-2397) >1000  90(73-110) >1000 AS1 >1000 >1000 >1000 >1000 AS49  1440(1250-2211) >1000  81(70-110) >1000 AS91 1005(916-1103) >1000 74(67-81) >1000 AS92 79(72-86)  >1000 19(12-29) >1000 AS93 >1000 >1000 86(78-93) >1000 AS95 >1000 >1000 36(27-47) >1000 AS99 700(650-760) >1000 10(8-13)  >1000 AS100 300(240-380) >1000 16(12-20) >1000 AS101 >1000 >1000 12(8-17)  >1000 AS89  955(896-1017) >1000 41(35-48) >1000 AS70 250(181-348) >1000 15(10-21) >1000 AS72 >1000 >1000 55(46-65) >1000 AS87 >1000 >1000  122(108-136) >1000 AS90 810(763-859) >1000 85(66-95) >1000 AS96 >1000 >1000 24(18-32) >1000 AS74 >1000 >1000 47(43-52) >1000 AS76 >1000 >1000 51(44-58) >1000 AS73 >1000 >1000 70(61-80) >1000 AS75 >1000 >1000 53(40-69) >1000 AS81 >1000 >1000 108(75-155) >1000 AS85 >1000 >1000 >1000 >1000 AS94 >1000 >1000 32(22-45) >1000 AS103    81    606    4.9 116

For use as a pharmaceutical preparation, Compound AS68 is particularly preferred due to its excellent affinity towards the A_(2B) receptor (K_(i)=5.5 nM) despite some significant A₁ adenosine receptor binding (K_(i)=200 nM). Due to strong cardiovascular effects compounds with significant A_(2A) binding are less preferred.

For use as a radioligand and where near total A_(2B) receptor selectivity is desired compounds such as AS13, AS15, AS16, AS17, AS28 and AS69 are preferred. All have relatively strong A_(2B) receptor binding (K_(i)=38-103 nM) but without significant binding for any of the other receptor subtypes.

FIGS. 1 through 4 show typical competition curves of compounds AS29, AS57, AS64 and AS68 at A₁, A_(2A), A_(2B), and A₃ A_(2B) and A₃ adenosine receptors.

Finally, to evaluate the regulation of adenylyl cyclase activity and to test whether the binding parameters correlated with the functional response, the IC₅₀ values were obtained for inhibition of cAMP production by antagonists. In particular, we evaluated the capability of the several compounds to inhibit NECA (100 nM)-stimulated cyclic AMP accumulation.

Table 2 summarizes the K, values obtained in [³H]-DPCPX binding to A_(2B) adenosine receptors and the IC₅₀ values for the inhibition of cAMP levels. Of the selected compounds, the most potent adenosine A_(2B) receptor antagonists were AS64 and AS68 (IC₅₀=38 and 88 nM, respectively). Compounds AS29 and AS57 show an IC₅₀ value of 93 and 95 nM, respectively (see also FIG. 7). Other tested compounds show an IC₅₀ value in the lower nanomolar range (IC₅₀=100-152 nM).

TABLE 2 Comparison of [³H]-DPCPX Binding to cAMP Levels [³H]-DPCPX binding to human A_(2B) Cyclic AMP assay-human receptors in HEK 293 cells A_(2b) receptors in CHO cells Ki (nM) IC₅₀ (nM) AS 11 35(27-45) 103(92-115)  AS 27 28(23-33) 128(114-144) AS 28 38(33-43) 120(103-140) AS 29 13(11-16) 93(84-102) AS 35 34(26-46) 152(136-170) AS 54 39(33-46) 136(115-161) AS 57 28(12-27) 95(90-101) AS 64 12(7-21)  88(82-95)  AS 65 20(16-25) 108(91-129)  AS 68  5.5(4.6-6.5) 38(29-51) 

Each value of Table 2 is the geometric mean (with 95% confidence limits in parentheses) of at least three separate experiments performed in duplicate.

The Spearman's rank correlation coefficient between affinity values of [³H]-DPCPX binding to A_(2B) adenosine receptor by selected compounds and the IC₅₀ values in the cAMP assay was 0.89 (P<0.01). A comparison of the K_(i) and IC₅₀ values indicated that high correlation exists between data obtained from binding and cAMP assays (FIG. 5).

Formulations

Formulations of the present invention for medical use comprise an active compound, i.e., a compound of formula (IA) or (IB) together with an acceptable carrier thereof and optionally other therapeutically active ingredients. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of formula (IA) or (IB) together with a pharmaceutically acceptable carrier thereof.

The formulations include, but are not limited to, those suitable for oral, rectal, topical or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred are those suitable for oral, parenteral or topical administration.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier and then, if necessary, shaping the product into desired unit dosage form.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.

A syrup or suspension may be made by adding the active compound to a concentrated, aqueous solution of a sugar, e.g., sucrose, to which may also be added any accessory ingredients. Such accessory ingredients) may include flavoring, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppository with a conventional carrier, e.g., cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany), for a suppository base.

Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparation of the active compound that is preferably isotonic with the blood of the recipient. Thus, such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline. Useful formulations also comprise concentrated solutions or solids containing the compound of formula (I) that upon dilution with an appropriate solvent give a solution suitable for parental administration above.

Topical formulations include ointments, creams, gels and lotions that may be prepared by conventional methods known in the art of pharmacy. In addition to the ointment, cream gel, or lotion base and the active ingredient, such topical formulation may also contain preservatives, perfumes, and additional active pharmaceutical agents.

Solutions for use as eyedrops are preferentially prepared by first aseptically mixing of all the necessary ingredients i.e. the active substance, salts and lubricant. If necessary the pH is adjusted to 5-7 using solutions of NaOH, KOH, HCl or boric acid. The solution is then sterilized by autoclaving or sterile filtration and filled on one dose packages.

Solutions can also be prepared by first preparing solutions of each of the ingredients and then sterilizing these solutions in the same manner as above before finally mixing and filling the solutions on one dose packages under aseptic conditions.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.

EXAMPLES-PHARMACEUTICAL FORMULATIONS

(A) Transdermal System - for 1000 patches Ingredients Amount Active compound 100 g Silicone fluid 450 g Colloidal silicon dioxide  2 g

The silicone fluid and active compound are mixed together and the colloidal silicone dioxide is added to increase viscosity. The material is then dosed into a subsequent heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin, and an impermeable backing membrane made of a polyester multi-laminate material. The resulting laminated sheet is than cut into 10 sq. cm patches

(B) Oral Tablet - For 1000 Tablets Ingredients Amount Active compound 50 g Starch 50 g Magnesium Stearate  5 g

The active compound and the starch are granulated with water and dried. Magnesium stearate is added to the dried granules and the mixture is thoroughly blended. The blended mixture is compressed into tablets.

(C) Injection - for 1000, 1 mL Ampules Ingredients Amount Active compound 10 g Buffering Agents q.s. Propylene glycol 400 mg Water for injection q.s. 1000 mL

The active compound and buffering agents are dissolved in the propylene glycol at about 50° C. The water for injection is then added with stirring and the resulting solution is filtered, filled into ampules, sealed and sterilized by autoclaving.

(D) Continuous Injection - for 1000 mL Ingredients Amount Active compound 10 g Buffering agents q.s. Water for injection q.s. 1000 mL

(E) Eye Drops - for 100 mL Ingredients Amount Active compound 0.01-1.0 g Sodium chloride 0.5-0.09 g Carbachol chloride 0.01-1.0 g Boric acid 1.15-3.0 g Water for injection q.s. 100 mL

The eyedrops according to the formulations suggested can be applied directly to the eye either upon need or 3-4 times daily.

An aerosol propellant suitable for use in an inhaler can be prepared similar to that described in U.S. Pat. No. 6,509,005 to Peart et al., which is incorporated by reference.

(F) Aerosol propellant Ingredients Amount Active compound 0.13% Ethanol   ~5% Hydrofluoroalkane propellant   95%

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents, modifications and variations to the specific embodiments of the invention described herein. For example, other excipients may be utilized in preparing the pharmaceutical formulations. In addition, some of the compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers and diastereomers as well as their racemic and resolved, enantiomerically pure or diastereomerically pure forms, and pharmaceutically acceptable salts thereof. Moreover, it will be appreciated that the general representation of such paired variables as R³ and R⁴, in compounds of formula (I), is not to be construed as to represent a particular orientation of the paired members. Accordingly, it is not intended that the present invention be limited to the specifics of the foregoing description of the preferred embodiments and example compounds, but rather as being limited only by the scope of the invention as defined in the claims appended hereto, including enantiomeric, diastereomeric and pharmaceutical salt forms.

REFERENCES

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1. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound of formula (I):

wherein R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl; R³ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl; A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons; X is an optionally substituted five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen; M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ to C₈)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or —S(O)₂—; G¹ and G² are independently CH or N; R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulflhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, —OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—; R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl; or a pharmaceutically acceptable salt thereof.
 2. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound selected from the group consisting of: 8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione; [3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)isoxazol-5-yl]methyl-benzoate; 8-(1-methyl-4-nitro-1H-pyrrol-2-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione; 4-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutanoic acid; tert-butyl 4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutylcarbamate; 4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutan-1-aminium chloride; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide; 2-(2,4-dichlorophenoxy)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; 2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-isobutylphenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide; 2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; 2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; (2S)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide; (2R)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide; {3-[(E)-2-(1,3-dipropyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]isoxazol-5-yl}methyl benzoate; 2-(4-chlorophenoxy)-N-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide; 2-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-chlorophenyl)acetamide; 2-(3,4-dimethoxyphenyl-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide; phenyl 4-[(E)-2-(7-methyl-1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]-1-methyl-1H-pyrrole-2-carboxylate; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]-2-phenylacetamide; 8-(5-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione; 8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide; 2-(2,3,4-trimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea; N-(3-chlorophenyl)-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea; 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; 2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-hydroxy-3-methoxyphenyl)acetamide; N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide; N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide; N-(4-fluorophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide; 2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-fluorophenyl)acetamide; 2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide; 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide; 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide; 2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide; 2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide; N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide; 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide; 1-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-3-(4-methoxyphenyl)-urea; 1,3-di-n-propyl-8-{5-[(4-sec-butyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{5-[(4-methyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{5-[(4-(morpholine-4-yl)-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{5-[(4-carboxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{5-[(3,4-dimethyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{5-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{5-[(pyridin-4-yl)-methoxyl-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxyl-2-methyl-2H-pyrazole-3-yl}-xanthine; 8-(5-{2-[4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; 1,3-di-n-propyl-8-{5-[2-oxo-2-(4-methyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 8-(5-{2-[4-(4-benzyl-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; 1,3-di-allyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-{3-[(3,4-methylendioxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine; 1,3-di-n-propyl-8-{3-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine; 1,3-di-n-propyl-8-{3-[(4-fluoro-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine; 1,3-di-n-propyl-8-{3-[(4-methoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine; 1,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-methoxy]-pyridin-3-yl}-xanthine; 1,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-methoxy]-pyridazin-3-yl}-xanthine; N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-diallyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide; 1,3-di-n-propyl-8-{5-[(4-(ethoxycarbonyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; 1,3-di-n-propyl-8-(2-hydroxypyridin-5-yl)-xanthine; and 1,3-di-n-propyl-8-{5-[(4-(aminosulfonyl)phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine; or a pharmaceutically acceptable salt thereof.
 3. A method of treating asthma,which method comprises administering to a patient in need of treatment thereof an effective amount of a compound selected from the group consisting of: N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide; 2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide; 2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; 2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide; 2-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-chlorophenyl)acetamide; 2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]-2-phenylacetamide; 8-(5-amino-1-methyl-1H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide; N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea; N-(3-chlorophenyl)-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea; N-[5-(2,6-dioxo-1,3-dipropyl-2 3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea; 2-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; 2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide; 2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide; 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide; 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide; 2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide; N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide; and 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide; or a pharmaceutically acceptable salt thereof.
 4. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound selected from the group consisting of: 2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide; 2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; 2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide; 2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide; 8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione; N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide; N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide; and 2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide; or a pharmaceutically acceptable salt thereof.
 5. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound of formula (IA):

wherein R¹ and R² are independently (C₁ to C₃)alkyl or allyl; A is a carbon-carbon bond; X is selected from the group consisting of

M is selected from the group consisting of —NHC(O)CH₂—, —NHC(O)CH₂O—, —NHC(O)CH(CH₃)—, and —NHC(O)NH—; R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxy, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, nitro, hydroxy, CO₂H; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a heterocyclic fused ring in which either R⁴ and R⁵ or R⁵ and R⁶ combined are —OCH₂O—; or a pharmaceutically acceptable salt thereof.
 6. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound of formula (IB):

wherein R¹ and R² are independently (C₁ to C₄)alkyl; A is a carbon-carbon bond; X is selected from the group consisting of

M is —OCH₂C(O)NH—; G¹ and G² are independently CH or N; R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxy, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, nitro, hydroxy, CO₂H; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a heterocyclic fused ring comprising —OCH₂O—; or a pharmaceutically acceptable salt thereof.
 7. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound of formula (IC):

wherein R¹ and R² are independently (C₁ to C₃)alkyl; R³ is hydrogen or methyl; A is selected from the group consisting of a carbon-carbon bond and —CH═CH—; X is

M is —CH₂OC(O)-—; R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxy, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, nitro, hydroxy, CO₂H; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or a pharmaceutically acceptable salt thereof.
 8. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound of formula (I):

wherein R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl; R³ is hydrogen, (C₁ to C₄) alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl; A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons; X is a five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen, wherein the heteroaromatic ring may be optionally substituted by one or two substituents selected from the group consisting of lower alkyl, amino, hydroxy, alkyloxy, acyloxy and acylamino; M is a (C₁ to C₈)alkylene, (C₂ to C₈)alkenylene, or (C₂ to C₈)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R⁷)—, —S—, —S(O)—, or —S(O)₂—; or a carbon substituted with a lower alkyl group; G¹ and G² are independently CH or N; R⁴, R⁵ and R⁶ are independently hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, (C₂ to C₅)alkynyl, optionally substituted (C₆ to C₁₀)aryl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulflhydryl, S(O)alkyl, S(O)₂alkyl, CO₂H, SO₃H; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur; or taken together with the carbon atoms to which they are attached either R⁴ and R⁵ or R⁵ and R⁶ form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH₂O—, —OCH(R⁷)O—, —OC(R⁷)₂O—, —OCH₂CH₂O—, —OCH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂—; R⁷ is hydrogen, (C₁ to C₄)alkyl, (C₂ to C₅)alkenyl, or (C₂ to C₅)alkynyl; or a pharmaceutically acceptable salt thereof.
 9. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound of formula (I):

wherein R¹ and R² are each n-propyl; R³ is hydrogen; A is a carbon-carbon bond; X is

M is —NHC(O)CH₂—; G¹ and G² are each CH; R⁴ and R⁶ are hydrogen; R⁵ is benzyloxy: or a pharmaceutically acceptable salt thereof.
 10. A method of treating asthma, which method comprises administering to a patient in need of treatment thereof an effective amount of a compound of formula (III):

wherein R¹ and R² are independently hydrogen, (C₁ to C₈)alkyl, (C₂ to C₈)alkenyl, (C₂ to C₈)alkynyl, (C₇ to C₁₄)aralkyl, (C₈ to C₁₄)aralkenyl, or (C₈ to C₁₄)aralkynyl; R⁸ is phenyl, halogen substituted phenyl, (C₁ to C₈)alkyl, or benzyl; or a pharmaceutically acceptable salt thereof. 